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Simple Summary: Head and neck cancer (HNC) is an aggressive form of cancer that affects hundreds of thousands of people worldwide and has a relatively poor prognosis. In the last decade, new therapeutics designed to enhance a patient's immune system have been approved for use, but HNC has developed many different methods that help it escape the immune system. The existing immunotherapies target only one of these mechanisms, allowing HNC to utilize others to continue to elude the immune system. This review details the various strategies used by HNC to escape the immune response, dividing them into four general categories: evade, resist, inhibit, and recruit. Each of the immune escape mechanisms represents a potential immunotherapy target that could be used to treat HNC. Head and neck cancers (HNCs) arise from the mucosal lining of the aerodigestive tract and are often associated with alcohol use, tobacco use, and/or human papillomavirus (HPV) infection. Over 600,000 new cases of HNC are diagnosed each year, making it the sixth most common cancer worldwide. Historically, treatments have included surgery, radiation, and chemotherapy, and while these treatments are still the backbone of current therapy, several immunotherapies have recently been approved by the Food and Drug Administration (FDA) for use in HNC. The role of the immune system in tumorigenesis and cancer progression has been explored since the early 20th century, eventually coalescing into the current three-phase model of cancer immunoediting. During each of the three phases—elimination, equilibrium, and escape—cancer cells develop and utilize multiple strategies to either reach or remain in the final phase, escape, at which point the tumor is able to grow and metastasize with little to no detrimental interference from the immune system. In this review, we summarize the many strategies used by HNC to escape the immune system, which include ways to evade immune detection, resist immune cell attacks, inhibit immune cell functions, and recruit pro-tumor immune cells. [ABSTRACT FROM AUTHOR]

Abstract Background Much is known about tumor infiltrating lymphocytes (Tils) in primary breast cancer, as this has been the focus of much research in recent years, but regarding recurrent breast cancer, only few studies have been done. Our aim was to compare the quantities of Tils in primary breast carcinomas and their corresponding recurrences and to analyze the differences in the tumor Tils compositions in correlations with recurrence-free times and the clinicopathology of the tumor. Methods One hundred thirty-seven breast cancer patients self-paired for primary- tumor-recurrence were divided into three groups based on the length of the recurrence-free interval. H&E-staining and immunohistochemical staining with antiCD3, antiCD4, antiCD8 and antiCD56 were performed. Differences in Tils between primaries and recurrences, between the recurrence-free interval groups, and between different clinicopathologic parameters were statistically analyzed. Results Fewer stromal CD3+, CD8+ and CD56+ lymphocytes were found at recurrences compared to the primaries. No significant change in the percentage of CD4+ stromal lymphocytes. ER-negative primaries, PR-negative or HER2-positive tumors had more Tils in some subgroups. Ductal primaries had more Tils than lobular primaries and G3 tumors had more Tils than lower-grade tumors. The corresponding differences at recurrences could either not be detected or they were reversed. The fastest recurring group had generally more Tils than the slower groups. Conclusions CD4+ cell numbers did not decline from primary to recurrence in contrast to all other subclasses of lymphocytes. The proportion of CD4+ cells was higher in recurrences than in primaries. Tumors with a higher grade and proliferation rate had higher percentages of Tils. HER2+ and hormone receptor negative tumors tended to have higher Tils scores. In recurrences these differences were not seen or they were reversed.

Breast cancer (BC) and ovarian cancer (OC) are among the most common and deadly cancers affecting women worldwide. Both are complex diseases with marked heterogeneity. Despite the induction of screening programs that increase the frequency of earlier diagnosis of BC, at a stage when the cancer is more likely to respond to therapy, which does not exist for OC, more than 50% of both cancers are diagnosed at an advanced stage. Initial therapy can put the cancer into remission. However, recurrences occur frequently in both BC and OC, which are highly cancer-subtype dependent. Therapy resistance is mainly attributed to a rare subpopulation of cells, named cancer stem cells (CSC) or tumor-initiating cells, as they are capable of self-renewal, tumor initiation, and regrowth of tumor bulk. In this review, we will discuss the distinctive markers and signaling pathways that characterize CSC, their interactions with the tumor microenvironment, and the strategies they employ to evade immune surveillance. Our focus will be on identifying the common features of breast cancer stem cells (BCSC) and ovarian cancer stem cells (OCSC) and suggesting potential therapeutic approaches. [ABSTRACT FROM AUTHOR]

Lynch syndrome (LS) is the most common inherited cancer syndrome. It is inherited via a monoallelic germline variant in one of the DNA mismatch repair (MMR) genes. LS carriers have a broad 30% to 80% risk of developing various malignancies, and more precise, individual risk estimations would be of high clinical value, allowing tailored cancer prevention and surveillance. Due to MMR deficiency, LS cancers are characterized by the accumulation of frameshift mutations leading to highly immunogenic frameshift peptides (FSPs). Thus, immune surveillance is proposed to inhibit the outgrowth of MMR‐deficient cell clones. Recent studies have shown that immunoediting during the evolution of MMR‐deficient cancers leads to a counter‐selection of highly immunogenic antigens. The immunogenicity of FSPs is dependent on the antigen presentation. One crucial factor determining antigen presentation is the HLA genotype. Hence, a LS carrier's HLA genotype plays an important role in the presentation of FSP antigens to the immune system, and may influence the likelihood of progression from precancerous lesions to cancer. To address the challenge of clarifying this possibility including diverse populations with different HLA types, we have established the INDICATE initiative (Individual cancer risk by HLA type, http://indicate-lynch.org/), an international network aiming at a systematic evaluation of the HLA genotype as a possible cancer risk modifier in LS. Here we summarize the current knowledge on the role of HLA type in cancer risk and outline future research directions to delineate possible association in the scenario of LS with genetically defined risk population and highly immunogenic tumors. [ABSTRACT FROM AUTHOR]

The main function of the immune system is to protect against infectious pathogens and to ensure tissue homeostasis. The latter function includes preventing autoimmune reactions, tolerizing cells to nonpathogenic environmental microorganisms, and eliminating apoptotic/damaged, transformed, or neoplastic cells. The process of carcinogenesis and tumor development and the role of the immune system in inhibiting progression of cancer have been the subject of intense research since the end of the 20th century and resulted in formulation of the cancer immunoediting hypothesis. The hypothesis postulates three steps in oncogenesis: 1) elimination – corresponding to immunosurveillance, 2) equilibrium in which the growth of transformed or neoplastic cells is efficiently controlled by immune effector mechanisms, and 3) escape in which cancer progresses due to an ineffective antitumor response. In parallel, a new field of science – immune-oncology – has arisen. Attempts are also being made to quantify intra-tumoral and peritumoral T cell infiltrations and to define optimal immunological parameters for prognostic/predictive purposes in several types of cancer. The knowledge of relationships between the tumor and the immune system has been and is practically exploited therapeutically in the clinic to treat cancer. Immunotherapy is a standard or supplementary treatment in various types of cancer.

Lung adenocarcinomas manifesting as subsolid nodules (SSN‐LUADs) possess distinct dormant behaviour. This study was designed to compare the immune landscapes of normal lungs (nLungs), SSN‐LUADs and LUADs manifesting as solid nodules (SN‐LUADs) so as to better understand the status of anti‐tumour immunity in SSN‐LUADs. Mass cytometry by time‐of‐flight analysis was performed on 299, 570 single cells from nLung, SSN‐LUAD and SN‐LUAD tissues. The immune cells were identified by phenotype, and the percentages of different immune cell subclusters were compared between SSN‐LUADs, SN‐LUADs and nLungs. Elevated percentage of CD8+ T cells were identified in SSN‐LUADs compared with in nLungs and SN‐LUADs. Elevated CD56bright NK cells and decreased CD56dim NK cells were identified in both SSN‐LUADs and SN‐LUADs compared with in nLungs. The immune landscape of SSN‐LUAD fits the theory of equilibrium phase of immunoediting, thus functional adaptive anti‐tumour immunity but impaired innate anti‐tumour immunity potentially contributes to the maintaining of its dormant behaviour. [ABSTRACT FROM AUTHOR]

Background: Much is known about tumor infiltrating lymphocytes (Tils) in primary breast cancer, as this has been the focus of much research in recent years, but regarding recurrent breast cancer, only few studies have been done. Our aim was to compare the quantities of Tils in primary breast carcinomas and their corresponding recurrences and to analyze the differences in the tumor Tils compositions in correlations with recurrence-free times and the clinicopathology of the tumor. Methods: One hundred thirty-seven breast cancer patients self-paired for primary- tumor-recurrence were divided into three groups based on the length of the recurrence-free interval. H&E-staining and immunohistochemical staining with antiCD3, antiCD4, antiCD8 and antiCD56 were performed. Differences in Tils between primaries and recurrences, between the recurrence-free interval groups, and between different clinicopathologic parameters were statistically analyzed. Results: Fewer stromal CD3+, CD8+ and CD56+ lymphocytes were found at recurrences compared to the primaries. No significant change in the percentage of CD4+ stromal lymphocytes. ER-negative primaries, PR-negative or HER2-positive tumors had more Tils in some subgroups. Ductal primaries had more Tils than lobular primaries and G3 tumors had more Tils than lower-grade tumors. The corresponding differences at recurrences could either not be detected or they were reversed. The fastest recurring group had generally more Tils than the slower groups. Conclusions: CD4+ cell numbers did not decline from primary to recurrence in contrast to all other subclasses of lymphocytes. The proportion of CD4+ cells was higher in recurrences than in primaries. Tumors with a higher grade and proliferation rate had higher percentages of Tils. HER2+ and hormone receptor negative tumors tended to have higher Tils scores. In recurrences these differences were not seen or they were reversed. [ABSTRACT FROM AUTHOR]

The HLA system represents a central component of the antigen presentation machinery. As every patient possesses a defined set of HLA molecules, only certain antigens can be presented on the cell surface. Thus, studying HLA type‐dependent antigen presentation can improve the understanding of variation in susceptibility to various diseases, including infectious diseases and cancer. In archival formalin‐fixed paraffin‐embedded (FFPE) tissue, the HLA type is difficult to analyze because of fragmentation of DNA, hindering the application of commonly used assays that rely on long DNA stretches. Addressing these difficulties, we present a refined approach for characterizing presence or absence of HLA‐A*02, the most common HLA‐A allele in the Caucasian population, in archival samples. We validated our genotyping strategy in a cohort of 90 samples with HLA status obtained by an NGS‐based method. 90% (n = 81) of the samples could be analyzed with the approach. For all of them, the presence or absence of HLA‐A*02 alleles was correctly determined with the method, demonstrating 100% sensitivity and specificity (95% CI: 91.40%–100% and 91.19%–100%). Furthermore, we provide an example of application in an independent cohort of 73 FFPE microsatellite‐unstable (MSI) colorectal cancer samples. As MSI cancer cells encompass a high number of mutations in coding microsatellites, leading to the generation of highly immunogenic frameshift peptide antigens, they are ideally suited for studying relations between the mutational landscape of tumor cells and interindividual differences in the immune system, including the HLA genotype. Overall, our method can help to promote studying HLA type‐dependency during the pathogenesis of a wide range of diseases, making archival and historic tissue samples accessible for identifying HLA‐A*02 alleles. [ABSTRACT FROM AUTHOR]

Although neoantigens are one of the most favorable targets in cancer immunotherapy, it is less versatile and costly to apply neoantigen‐derived cancer vaccines to patients due to individual variation. It is, therefore, important to find highly immunogenic antigens between tumor‐specific or associated antigens that are shared among patients. Considering the cancer immunoediting theory, immunogenic tumor cells cannot survive in the early phase of tumor progression including two processes: elimination and equilibrium. We hypothesized that highly immunogenic molecules are allowed to be expressed in tumor cells after an immune suppressive tumor microenvironment was established, if these molecules contribute to tumor survival. In the current study, we focused on TWIST1 as a candidate for highly immunogenic antigens because it is upregulated in tumor cells under hypoxia and promotes tumor metastasis, which is observed in the late phase of tumor progression. We demonstrated that TWIST1 had an immunogenic peptide sequence TWIST1140–162, which effectively activated TWIST1‐specific CD4+ T‐cells. In a short‐term culture system, we detected more TWIST1‐specific responses in breast cancer patients compared with in healthy donors. Vaccination with the TWIST1 peptide also showed efficient expansion of TWIST1‐reactive HTLs in humanized mice. These findings indicate that TWIST1 is a highly immunogenic shared antigen and a favorable target for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) exerts key effects on tumor development, progression and treatment. Therefore, a quantitative understanding of various cellular and molecular interactions in the TME is very important. In this study, we combined a dynamic model and data analysis to quantitatively explore how microenvironmental factors influence tumor growth and three phases of cancer immunoediting. First, we presented a model system of partial differential equations (PDEs) using four main types of cells within the microenvironment of solid tumors and used two sets of published experimental data to validate the model. Accordingly, the partial rank correlation coefficient (PRCC) was calculated to identify the sensitive parameters related to significant biological processes. Furthermore, numerical simulations indicated that the power of tumor proliferation exerts a substantial effect on the state of malignancy, but tumor control is achieved by adjusting sensitive microenvironmental factors, such as immune intensity and the proliferation of cancer-associated fibroblasts (CAFs). Moreover, we used two indicators to quantify three states, i.e., elimination, equilibrium and escape from cancer immunoediting. The quantitative analysis of the TME revealed that immune cells and CAFs dynamically guide the transition of the three states of immunoediting, namely, how these related factors affect the capacity of the immune system to eliminate developing tumor cells, hold them in an equilibrium state, or facilitate their expanded growth. These quantitative results provide new insights into how various microenvironmental changes mediate both natural and therapeutically induced cancer immunoediting responses. [ABSTRACT FROM AUTHOR]

Since the late 19th century, the immune system has increasingly garnered interest as a novel avenue for cancer therapy, particularly given scientific breakthroughs in recent decades delineating the fundamental role of the immune system in tumorigenesis. The immunoediting hypothesis has articulated this role, describing three phases of the tumor-immune system interaction: Elimination, Equilibrium, and Escape wherein tumors progress from active immunologic surveillance and destruction through dynamic immunologic stasis to unfettered growth. The primary goals of immunotherapy are to restrict and revert progression through these phases, thereby improving the immune system's ability to control tumor growth. In this review, we detail the development and foundation of the cancer immunoediting hypothesis and apply this hypothesis to the dynamic immunotherapy field that includes checkpoint blockade, vaccine therapy, and adoptive cell transfer. [ABSTRACT FROM AUTHOR]

Immune selection drives tumor cells to acquire refractory phenotypes. We previously demonstrated that cytotoxic T lymphocyte (CTL)-mediated immune pressure enriches NANOG+ tumor cells with stem-like and immune-refractory properties that make them resistant to CTLs. Here, we report that the emergence of refractory phenotypes is highly associated with an aberrant macroautophagic/autophagic state of the NANOG+ tumor cells and that the autophagic phenotype arises through transcriptional induction of MAP1LC3B/LC3B by NANOG. Furthermore, we found that upregulation of LC3B expression contributes to an increase in EGF secretion. The subsequent hyperactivation of EGFR-AKT signaling rendered NANOG+ tumor cells resistant to CTL killing. The NANOG-LC3B-p-EGFR axis was preserved across various types of human cancer and correlated negatively with the overall survival of cervical cancer patients. Inhibition of LC3B in immune-refractory tumor models rendered tumors susceptible to adoptive T-cell transfer, as well as PDCD1/PD-1 blockade, and led to successful, long-term control of the disease. Thus, our findings demonstrate a novel link among immune-resistance, stem-like phenotypes, and LC3B-mediated autophagic secretion in immune-refractory tumor cells, and implicate the LC3B-p-EGFR axis as a central molecular target for controlling NANOG+ immune-refractory cancer. Abbreviations: ACTB: actin beta; ATG7: autophagy related 7; BafA1: bafilomycin A1; CASP3: caspase 3; CFSE: carboxyfluorescein succinimidyl ester; ChIP: chromatin immunoprecipitation; CI: confidence interval; CIN: cervical intraepithelial neoplasia; CSC: cancer stem cell; CTL: cytotoxic T lymphocyte; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; FIGO: International Federation of Gynecology and Obstetrics; GFP: green fluorescent protein; GZMB: granzyme B; HG-CIN: high-grade CIN; IHC: immunohistochemistry; LG-CIN: low-grade CIN; LN: lymph node; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MCL1: myeloid cell leukemia sequence 1; MLANA/MART-1: melanoma antigen recognized by T cells 1; MUT: mutant; NANOG: Nanog homeobox; PDCD1/PD-1: programmed cell death 1; PMEL/gp100: premelanosome protein; RTK: receptor tyrosine kinase; TMA: tissue microarray; WT: wild type [ABSTRACT FROM AUTHOR]

Recent studies have revealed that tumor cells decrease their immunogenicity by epigenetically repressing the expression of highly immunogenic antigens to survive in immunocompetent hosts. We hypothesized that these epigenetically hidden "stealth" antigens should be favorable targets for cancer immunotherapy due to their high immunogenicity. To identify these stealth antigens, we treated human lung cell line A549 with DNA methyltransferase inhibitor 5‐aza‐2′‐deoxycytidine (5Aza) and its prodrug guadecitabine for 3 d in vitro and screened it using cDNA microarray analysis. We found that the gene encoding sperm equatorial segment protein 1 (SPESP1) was re‐expressed in cell lines including solid tumors and leukemias treated with 5Aza, although SPESP1 was not detected in untreated tumor cell lines. Using normal human tissue cDNA panels, we demonstrated that SPESP1 was not detected in normal human tissue except for testis and placenta. Moreover, we found using immunohistochemistry SPESP1 re‐expression in xenografts in BALB/c‐nu/nu mice that received 5Aza treatment. To assess the antigenicity of SPESP1, we stimulated human CD4+ T‐cells with a SPESP1‐derived peptide designed using a computer algorithm. After repetitive stimulation, SPESP1‐specific helper T‐cells were obtained; these cells produced interferon‐γ against HLA‐matched tumor cell lines treated with 5Aza. We also detected SPESP1 expression in freshly collected tumor cells derived from patients with acute myeloid leukemia or lung cancer. In conclusion, SPESP1 can be classified as a stealth antigen, a molecule encoded by a gene that is epigenetically silenced in tumor cells but serves as a highly immunogenic antigen suitable for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) play a crucial role in the complex interplay between tumor cells and the immune system. During the elimination phase of cancer immunoediting, immunostimulatory DCs are critical for the control of tumor growth. During the escape phase, regulatory DCs sustain tumor tolerance and contribute to the development of the immunosuppressive tumor microenvironment that characterizes this phase. Moreover, increasing evidence indicates that DCs are also critical for the success of cancer immunotherapy. Hence, there is increasing need to fully characterize DC subsets and their activatory/inhibitory profile in cancer patients. In this review, we describe the role played by different DC subsets in the different phases of cancer immunoediting, the function exerted by different activatory and inhibitory molecules expressed on DC surface, and the cytokines produced by distinct DC subsets, in order to provide an overview on the DC features that may be useful to be assessed when dealing with the flow cytometric characterization of DCs in cancer patients. © 2020 International Society for Advancement of Cytometry [ABSTRACT FROM AUTHOR]

Aim: To characterize, by means of univariate and multivariate approaches, the T helper (Th)-1 and Th-2 responses during the different phases of tumor immunoediting. Materials & methods: We used a multivariate principal component analysis applied to analyze the joint behavior of serum concentrations of IFN-γ, IL-2, IL-10 and IL-4, during the different phases of tumor immunoediting, in CBi/L mice challenged with M-406 mammary adenocarcinoma. Results & conclusion: Animals in equilibrium phase showed the widest variations in values of the four cytokines. In this experimental model, the role of IFN-γ would be related to tumor growth and progression, while IL-10 would participate in the antitumor immune response.

Adoptive T cell therapy (ACT) is a rapidly evolving therapeutic approach designed to harness T cell specificity and function to fight diseases. Based on the evidence that T lymphocytes can mediate a potent anti-tumor response, initially ACT solely relied on the isolation, in vitro expansion, and infusion of tumor-infiltrating or circulating tumor-specific T cells. Although effective in a subset of cases, in the first ACT clinical trials several patients experienced disease progression, in some cases after temporary disease control. This evidence prompted researchers to improve ACT products by taking advantage of the continuously evolving gene engineering field and by improving manufacturing protocols, to enable the generation of effective and long-term persisting tumor-specific T cell products. Despite recent advances, several challenges, including prioritization of antigen targets, identification, and optimization of tumor-specific T cell receptors, in the development of tools enabling T cells to counteract the immunosuppressive tumor microenvironment, still need to be faced. This review aims at summarizing the major achievements, hurdles and possible solutions designed to improve the ACT efficacy and safety profile in the context of liquid and solid tumors.

Abstract Background Immunotherapy is at the forefront of modern oncologic care. Various novel therapies have targeted all three layers of tumor biology: tumor, niche, and immune system with a range of promising results. One emerging class in both primary and salvage therapy is oncolytic viruses. This therapy offers a multimodal approach to specifically and effectively target and destroy malignant cells, though a barrier oncoviral therapies have faced is a limited therapeutic response to currently delivery techniques. Main body The ability to deliver therapy tailored to specific cellular targets at the precise locus in which it would have its greatest impact is a profound development in anti-cancer treatment. Although immune checkpoint inhibitors have an improved tolerability profile relative to cytotoxic chemotherapy and whole beam radiation, severe immune-related adverse events have emerged as a potential limitation. These include pneumonitis, pancreatitis, and colitis, which are relatively infrequent but can limit therapeutic options for some patients. Intratumor injection of oncolytic viruses, in contrast, has a markedly lower rate of serious adverse effects and perhaps greater specificity to target tumor cells. Early stage clinical trials using oncolytic viruses show induction of effector anti-tumor immune responses and suggest that such therapies could also morph and redefine both the local target cells’ niche as well as impart distant effects on remote cells with a similar molecular profile. Conclusion It is imperative for the modern immuno-oncologist to understand the biological processes underlying the immune dysregulation in cancer as well as the effects, uses, and limitations of oncolytic viruses. It will be with this foundational understanding that the future of oncolytic viral therapies and their delivery can be refined to forge future horizons in the direct modulation of the tumor bed.

Adoptive T cell therapy (ACT) is a rapidly evolving therapeutic approach designed to harness T cell specificity and function to fight diseases. Based on the evidence that T lymphocytes can mediate a potent anti-tumor response, initially ACT solely relied on the isolation, in vitro expansion, and infusion of tumor-infiltrating or circulating tumor-specific T cells. Although effective in a subset of cases, in the first ACT clinical trials several patients experienced disease progression, in some cases after temporary disease control. This evidence prompted researchers to improve ACT products by taking advantage of the continuously evolving gene engineering field and by improving manufacturing protocols, to enable the generation of effective and long-term persisting tumor-specific T cell products. Despite recent advances, several challenges, including prioritization of antigen targets, identification, and optimization of tumor-specific T cell receptors, in the development of tools enabling T cells to counteract the immunosuppressive tumor microenvironment, still need to be faced. This review aims at summarizing the major achievements, hurdles and possible solutions designed to improve the ACT efficacy and safety profile in the context of liquid and solid tumors. [ABSTRACT FROM AUTHOR]

For decades, cardiovascular diseases and tumours have been among the infamous diseases that most affect people around the world. Both are accompanied by characteristic immune manifestations, which are in principle identical, but differ in a number of essential aspects. Even in the eighties of the last century, the prevailing opinion was that atherosclerosis had multifactorial genesis, i.e. that the causes and development of the pathological process in arteries resulting in the deposition of cholesteric plaque was contributed to several causes of the external and internal environment. External atherogenic causes included high energy intake (excessive consumption of animal fats and carbohydrates), lack of physical activity, smoking and polluted environment, whereas genetically determined defects of lipid metabolism represented endogenous factors. Infectious causes and the role of immunity were practically not considered. The involvement of immunity in the tumour process has been the subject of reflection even since the early twentieth century. At that time, immunity was only known to be directed against infectious agents, but virtually nothing was known about the structural nature and function of the immune system. Later on, it has been shown that immunity can have a dual function in connection to tumours: it destroys and suppresses tumour cells, but also promotes tumour growth by selecting more viable tumour cells. It is just the participation of the immunity in the tumour process that enables new possibilities for treating tumours by providing biological therapy (immunotherapy). [ABSTRACT FROM AUTHOR]

The driver mutations in exon 9 of the calreticulin protein have only been identified in patients with myeloid cancers. We recently demonstrated that healthy individuals display strong and frequent T-cell responses towards this mutation. This memory T-cell response is likely evidence of the elimination of mutated cells in healthy individuals.

The immune system plays a dual role in cancer. It conveys protective immunity but also facilitates malignant progression, either by sculpting tumor immunogenicity or by creating a microenvironment that can stimulate tumor outgrowth or aid in a subsequent metastatic cascade. Innate lymphoid cells (ILCs) embody this functional heterogeneity, although the nature of their responses in cancer has only recently begun to be unveiled. We provide an overview of recent insights into the role of ILCs in cancer. We also discuss how ILCs fit into the conceptual framework of cancer immunoediting, which integrates the dual role of the immune system in carcinogenesis. A broader understanding of their relevance in cancer is essential towards the design of successful therapeutic strategies. Highlights ILCs have been implicated in both tumor-suppressing and tumor-promoting activities. The possibility to enhance and/or reorient their tumor-suppressing and/or tumor-promoting activities, respectively, provides an opportunity to design putative successful therapeutic approaches. Insights into how cancer cells regulate ILC function represent an important area of unfulfilled need towards the design of therapeutic strategies. An improved understanding of the biology of ILCs could help in the management of immunotherapy-related side effects arising from treatments, including those stemming from immune checkpoint blockade therapy. [ABSTRACT FROM AUTHOR]

The cancer stem cell (CSC) paradigm posits that specific cells within a tumor, so-called CSC-like cells, have differing levels of tumorigenicity and chemoresistance. Original studies of CSCs identified them in human cancers and utilized mouse xenograft models to define the cancer initiating properties of these cells, thereby hampering the understanding of how immunity could affect CSCs. Indeed, few studies have characterized CSCs in the context of cancer immunoediting, and it is currently not clear how immunity could impact on the levels or stem-like behavior of CSCs. Using the well-studied 3′methylcholanthrene (MCA) model of primary sarcoma formation, we have defined a CSC-like population within MCA-induced sarcomas as expressing high levels of stem cell antigen-1 (Sca-1) and low levels of CD90. These Sca-1+CD90− CSC-like cells had higher tumor initiating ability, could spontaneously give rise to Sca-1-negative cells, and formed more sarcospheres than corresponding non-CSC-like cells. Moreover, when examining MCA-induced sarcomas that were in the equilibrium phase of cancer growth, higher levels of CSC-like cells were found compared to MCA-induced sarcomas in the escape phase of cancer progression. Notably, CSC-like cells also emerged during escape from anti-PD-1 or anti-CTLA4 therapy, thus suggesting that CSC-like cells could evade immune therapy. Finally, we demonstrate that paradoxically, interferon (IFN)-γ produced in vivo by immune cells could promote the emergence of CSC-like cells. Our findings define the existence of a Sca1+CD90− CSC-like population in the MCA-sarcoma model capable of differentiation, tumorsphere formation, and increased tumor initiation in vivo. These cells may also act as mediators of immune resistance during cancer immunoediting and immune therapy.

Although papillary thyroid cancer (PTC) is curable with excellent survival rate, patients with dedifferentiated PTC suffer the recurrence or death. As cancer immune escape plays a critical role in cancer progression, we aimed to investigate the relationship between differentiation and immune landscape of PTC and its implications for immunotherapy. Using The Cancer Genome Atlas data, we estimated the immune cell enrichment scores and overall immune infiltration, ImmuneScore, to characterize the immune landscape of PTC. Thyroid differentiation score (TDS) was calculated from 16 thyroid function genes. We demonstrated that ImmuneScore had a significant negative correlation with TDS, and BRAFV600E+ tumors showed significantly low TDS and high ImmuneScore. Enrichment scores of myeloid cells and B-cells were negatively correlated with TDS, while those of plasma cells were positively correlated with TDS. In addition, the association between TDS, ImmuneScore and immunosuppressive markers (CTLA-4, PD-L1, HLA-G) were evaluated according to BRAFV600E status. All immunosuppressive markers expression had a significant negative correlation with TDS, and they were significantly higher in BRAFV600E+ status. Subgroups were divided by median values of TDS and ImmuneScore, and immunosuppressive markers of these subgroups were compared. The immunosuppressive markers expression was the highest in high ImmuneScore and low TDS subgroup. Furthermore, ImmuneScore had a significant association with recurrence-free survival, irrespective of clinicopathologic factors including BRAFV600E status. These findings based on gene expression data illuminate the immune landscape of PTC and its association with TDS, immunosuppressive markers and recurrence. Our results would be extended to investigate immunotherapeutic approaches in PTC. [ABSTRACT FROM AUTHOR]

Annexin A1 is a multifunctional protein characterised by its actions in modulating the innate and adaptive immune response. Accumulating evidence of altered annexin A1 expression in many human tumours raises interest in its functional role in cancer biology. In breast cancer, altered annexin A1 expression levels suggest a potential influence on tumorigenic and metastatic processes. However, reports of conflicting results reveal a relationship that is much more complex than first conceptualised. In this review, we explore the diverse actions of annexin A1 on breast tumour cells and various host cell types, including stromal immune and structural cells, particularly in the context of cancer immunoediting. [ABSTRACT FROM AUTHOR]

Although most cancer types have been viewed as immunologically silent until recently, it has become increasingly clear that the immune system plays key roles in the course of tumor development. Remarkable progress towards understanding cancer immunogenicity and tumor-immune system interactions has revealed important implications for the design of novel immune-based therapies. Natural immune responses, but also therapeutic interventions, can modulate the tumor phenotype due to selective outgrowth of resistant subtypes. This is the result of heterogeneity of tumors, with genetic instability as a driving force, and obviously changes the immunogenicity of tumors. In this review, we discuss the immunogenicity of colorectal cancer (CRC) in relation to tumor development and treatment. As most tumors, CRC activates the immune system in various ways, and is also capable of escaping recognition and elimination by the immune system. Tumor-immune system interactions underlie the balance between immune control and immune escape, and may differ in primary tumors, in the circulation, and in liver metastases of CRC. Since CRC immunogenicity varies between tumors and individuals, novel immune-based therapeutic strategies should not only anticipate the molecular profile, but also the immunological profile of a specific tumor. [ABSTRACT FROM AUTHOR]

Definitive experimental evidence from mouse cancer models and strong correlative clinical data gave rise to the Cancer Immunoediting concept that explains the dual host-protective and tumor-promoting actions of immunity on developing cancers. Tumor-specific neoantigens can serve as targets of spontaneously arising adaptive immunity to cancer and thereby determine the ultimate fate of developing tumors. Tumor-specific neoantigens can also function as optimal targets of cancer immunotherapy against established tumors. These antigens are derived from nonsynonymous mutations that occur during cellular transformation and, because they are foreign to the host genome, are not subject to central tolerance. In this review, we summarize the experimental evidence indicating that cancer neoantigens are the source of both spontaneously occurring and therapeutically induced immune responses against cancer. We also review the advances in genomics, bioinformatics, and cancer immunotherapy that have facilitated identification of neoantigens and have moved personalized cancer immunotherapies into clinical trials, with the promise of providing more specific, safer, more effective, and perhaps even more generalizable treatments to cancer patients than current immunotherapies. [ABSTRACT FROM AUTHOR]

Since it is known that the immune system affects tumor growth, it has been studied if immunotherapy can be developed to combat cancer. While some successes have been claimed, the increasing knowledge on tumor-immune interactions has, however, also shown the limitations of this approach. Tumors may show selective outgrowth of cells escaped from immune control. Escape variants arise spontaneously due to the genetically instable nature of tumor cells. This is one of the most obvious limitations of cancer immunotherapy. However, new therapies are becoming available, designed to respond to tumor-immune escape. [ABSTRACT FROM PUBLISHER]

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In the Sp6 mouse plasmacytoma model, a whole-cell vaccination with Sp6 cells expressing de novo B7-1 (Sp6/B7) induced anatomically localized and cytotoxic T cell ( CTL) -mediated protection against wild-type ( WT) Sp6. Both WT Sp6 and Sp6/B7 showed down-regulated expression of MHC H-2 Ld. Increase of H-2 Ld expression by cDNA transfection (Sp6/B7/Ld) raised tumour immune protection and shifted most CTL responses towards H-2 Ld-restricted antigenic epitopes. The tumour-protective responses were not specific for the H-2 Ld-restricted immunodominant AH1 epitope of the gp70 common mouse tumour antigen, although WT Sp6 and transfectants were able to present it to specific T cells in vitro. Gp70 transcripts, absent in secondary lymphoid organs of naive mice, were detected in immunized mice as well as in splenocytes from naive mice incubated in vitro with supernatants of CTL-lysed Sp6 cell cultures, containing damage-associated molecular patterns (DAMPs). It has been shown that Toll-like receptor triggering induces gp70 expression. Damage-associated molecular patterns are released by CTL-mediated killing of Sp6/B7-Sp6/B7/Ld cells migrated to draining lymph nodes during immunization and may activate gp70 expression and presentation in most resident antigen-presenting cells. The same could also apply for Mus musculus endogenous ecotropic murine leukaemia virus 1 particles present in Sp6-cytosol, discharged by dying cells and superinfecting antigen-presenting cells. The outcome of such a massive gp70 cross-presentation would probably be tolerogenic for the high-affinity AH1-gp70-specific CTL clones. In this scenario, autologous whole-tumour-cell vaccines rescue tumour-specific immunoprotection by amplification of subdominant tumour antigen responses when those against the immune dominant antigens are lost. [ABSTRACT FROM AUTHOR]

Copyright of African Journal of Cancer / Journal Africain du Cancer is the property of Lavoisier and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Recent progress in tumor immunology has revealed that tumors generate immunologically restrained milieu during the process of their growth, which facilitates the escape of tumors from host immune systems. Immune checkpoint molecules, which transduce co-inhibitory signals to immuno-competent cells, are one of the most important components conferring the immunosuppressive capacity in the tumor microenvironment. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1) are typical immune checkpoint molecules intimately involved in the suppression of anti-tumor immunity. Antibodies against those molecules have been developed, such as ipilimumab (anti-CTLA-4 antibody), nivolumab and pembrolizumab (anti-PD-1 antibody), and have been approved by regulatory agencies and used in some countries. Treatment with these antibodies demonstrates previously unobserved clinical efficacies superior to the conventional therapies. In this review, we first discuss the escape mechanisms of cancer from host immune systems, and then focus on the recent advances in immune checkpoint blockade therapy and on the new findings of related immune reactions, aiming to provide a better understanding of the novel cancer immunotherapies. [ABSTRACT FROM AUTHOR]

Aberrant glycosylation is a key feature of malignant transformation and reflects epigenetic and genetic anomalies among the multitude of molecules involved in glycan biosynthesis. Although glycan biosynthesis is not template bound, altered tumor glycosylation is not random, but associated with common glycosylation patterns. Evidence suggests that acquisition of distinct glycosylation patterns evolves from a 'microevolutionary' process conferring advantages in terms of tumor growth, tumor dissemination, and immune escape. Such glycosylation modifications also involve xeno- and hypersialylation. Xeno-autoantigens such as Neu5Gc-gangliosides provide potential targets for immunotherapy. Hypersialylation may display 'enhanced self' to escape immunosurveillance and involves several not mutually exclusive inhibitory pathways that all rely on protein-glycan interactions. A better understanding of tumor 'glycan codes' as deciphered by lectins, such as siglecs, selectins, C-type lectins and galectins, may lead to novel treatment strategies, not only in cancer, but also in autoimmune disease or transplantation. [ABSTRACT FROM AUTHOR]

It has been recently proposed that the two emerging hallmarks of cancer, namely altered glucose metabolism and immune evasion, may in fact be fundamentally linked. This connection comes from up-regulation of glycolysis by tumor cells, which can lead to active competition for resources in the tumor microenvironment between tumor and immune cells. Here it is further proposed that cancer stem cells (CSCs) can circumvent the anti-tumor immune response by creating a “protective shield” of non-stem cancer cells around them. This shield can protect the CSCs both by creating a physical barrier between them and cytotoxic lymphocytes (CTLs), and by promoting competition for the common resources, such as glucose, between non-stem cancer cells and CTLs. The implications of this hypothesis are investigated using an agent-based model, leading to a prediction that relative CSC to non-CSC ratio will vary depending on the strength of the host immune response. A discussion of possible therapeutic approaches concludes the paper, suggesting that a chemotherapeutic regimen consisting of regular pulsed doses, i.e., metronomic chemotherapy, would yield the best clinical outcome by removing the “protective shield” and thus allowing CTLs to most effectively reach and eliminate CSCs. [ABSTRACT FROM AUTHOR]

While persistent infection with oncogenic types of human Papillomavirus (HPV) is required for cervical epithelial cell transformation and cervical carcinogenesis, HPV infection alone is not sufficient to induce tumorigenesis. Only a minor fraction of HPV infections produce high-grade lesions and cervical cancer, suggesting complex host–virus interactions. Based on its pronounced immunoinhibitory properties, human leukocyte antigen (HLA)-G has been proposed as a possible prognostic biomarker and therapeutic target relevant in a wide variety of cancers and viral infections, but to date remains underexplored in cervical cancer. Given the possible influence of HLA-G on the clinical course of HPV infection, cervical lesions and cancer progression, a better understanding of HLA-G involvement in cervical carcinogenesis might contribute to two aspects of fundamental importance: 1. Characterization of a novel diagnostic/prognostic biomarker to identify cervical cancer and to monitor disease stage, critical for patient screening; 2. Identification of HLA-G-driven immune mechanisms involved in lesion development and cancer progression, leading to the development of strategies for modulating HLA-G expression for treatment purposes. Thus, this systematic review explores the potential involvement of HLA-G protein expression and polymorphisms in cervical carcinogenesis. [ABSTRACT FROM AUTHOR]

Increasing experimental evidence suggests that epigenetic and microenvironmental factors play a key role in cancer progression. In this respect, it is now generally recognized that the immune system can act as an additional selective pressure, which modulates tumor development and leads, through cancer immunoediting, to the selection for resistance to immune effector mechanisms. This may have serious implications for the design of effective anti-cancer protocols. Motivated by these considerations, we present a mathematical model for the dynamics of cancer and immune cells under the effects of chemotherapy and immunity-boosters. Tumor cells are modeled as a population structured by a continuous phenotypic trait, that is related to the level of resistance to receptor-induced cell death triggered by effector lymphocytes. The level of resistance can vary over time due to the effects of epigenetic modifications. In the asymptotic regime of small epimutations, we highlight the ability of the model to reproduce cancer immunoediting. In an optimal control framework, we tackle the problem of designing effective anti-cancer protocols. The results obtained suggest that chemotherapeutic drugs characterized by high cytotoxic effects can be useful for treating tumors of large size. On the other hand, less cytotoxic chemotherapy in combination with immunity-boosters can be effective against tumors of smaller size. Taken together, these results support the development of therapeutic protocols relying on combinations of less cytotoxic agents and immune-boosters to fight cancer in the early stages. [ABSTRACT FROM PUBLISHER]

Background Cancer immunoediting is a dynamic process composed of three phases: elimination (EL), equilibrium (EQ) and escape (ES) that encompasses the potential host-protective and tumorsculpting functions of the immune system throughout tumor development. Animal models are useful tools for studying diseases such as cancer. The present study was designed to characterize the interaction between mammary adenocarcinoma M-406 and CBi, CBi- and CBi/L inbred mice lines. Results The mammary adenocarcinoma M-406 developed spontaneously in a CBi mouse. CBi/L and CBi- mice were artificially selected for body conformation from CBi. When CBi mice are s.c. challenged with M-406, tumor growths exponentially in 100% of animals, while in CBi- the tumor growths briefly and then begins a rejection process in 100% of the animals. In CBi/L the growth of the tumor shows the three phases: 51.6% in ES, 18.5% in EQ and 29.8% in EL. Conclusions The results obtained support the conclusion that the system M-406 plus the inbred mouse lines CBi, CBi- and CBi/L, is a good murine model to study the process of tumor immunoediting. [ABSTRACT FROM AUTHOR]

Accumulated data from animal models and human cancer patients strongly support the concept that the immune system can identify and control nascent tumor cells in a process called cancer immunosurveillance. In addition, the immune system can also promote tumor progression through chronic inflammation, immunoselection of poorly immunogenic variants, and suppressing antitumor immunity. Together, the dual host-protective and tumor-promoting actions of immunity are referred to as cancer immunoediting. The current framework of cancer immunoediting is a dynamic process comprised of three distinct phases: elimination, equilibrium, and escape. Recently, we demonstrated that immunoselection by CD8+ T cells of tumor variants lacking strong tumor-specific antigens represents one mechanism by which cancer cells escape tumor immunity and points toward the future of personalized cancer therapy. [ABSTRACT FROM AUTHOR]

Upon activation, neutrophils release fibers composed of chromatin and neutrophil proteins termed neutrophil extracellular traps (NETs). NETs trap and kill microbes, activate dendritic cells and T cells, and are implicated in autoimmune and vascular diseases. Given the growing interest in the role of neutrophils in cancer immunoediting and the diverse function of NETs, we searched for NETs release by tumor-associated neutrophils (TANs). Using pediatric Ewing sarcoma (ES) as a model, we retrospectively examined histopathological material from diagnostic biopsies of eight patients (mean ± SD age of 11.5 ± 4.7 years). TANs were found in six patients and in two of those we identified NETs. These two patients presented with metastatic disease and despite entering complete remission after intensive chemotherapy had an early relapse. NETs were not identified in the diagnostic biopsies of two patients with localized disease and two with metastatic disease. This study is the first to show that ANs in ES are activated to make NETs, pointing to a possible role of NETs in cancer. [ABSTRACT FROM AUTHOR]

Abstract: Tumorigenesis implies adaptation of tumor cells to an adverse environment. First, developing tumors must acquire nutrients to ensure their rapid growth. Second, they must escape the attack from the host immune system. Recent studies suggest that these phenomena could be related and that tumor cell metabolism may propel tumor immune escape. Tumor cell metabolism tends to avoid mitochondrial activity and oxidative phosphorylation (OXPHOS), and largely relies on glycolysis to produce energy. This specific metabolism helps tumor cells to avoid the immune attack from the host by blocking or avoiding the immune attack. By changing their metabolism, tumor cells produce or sequester a variety of amino acids, lipids and chemical compounds that directly alter immune function therefore promoting immune evasion. A second group of metabolism-related modification targets the major histocompatibility complex-I (MHC-I) and related molecules. Tumor MHC-I presents tumor-associated antigens (TAAs) to cytotoxic T-cells (CTLs) and hence, sensitizes cancer cells to the cytolytic actions of the anti-tumor adaptive immune response. Blocking tumor mitochondrial activity decreases expression of MHC-I molecules at the tumor cell surface. And peroxynitrite (PNT), produced by tumor-infiltrating myeloid cells, chemically modifies MHC-I avoiding TAA expression in the plasma membrane. These evidences on the role of tumor cell metabolism on tumor immune escape open the possibility of combining drugs designed to control tumor cell metabolism with new procedures of anti-tumor immunotherapy. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy. [Copyright &y& Elsevier]

The aryl hydrocarbon receptor (AhR), a member of the PAS protein family, is found in organisms as diverse as Drosophila melanogaster, nematodes, and mammals. While several reviews have reported that AhR, once activated by agonist ligands, causes long-term effects such as modification of cell growth through cell cycle control, there is also recent evidence of its decisive role in immunosuppression. The most widely studied AhR agonist is 2,3,7,8-tetrachlorodibenzo-p-dioxin, which binds AhR with the highest known affinity, leading to profound suppression of both humoral and cellular immune responses, with praecox thymus involution, consequent thymocyte loss, and induction of T-cell apoptosis. Dioxin-AhR binding causes a decline in the number of dendritic cells and enhances apoptosis following their inappropriate activation. Dioxin-mediated activation of AhR also has a direct influence on the expansion of regulatory T-cells CD4+CD25+ FoxP3+ (T-regs) and an adverse affect on CD8+ T-cell responses. Dioxin released from industrial and waste incinerators over the last few decades has caused widespread contamination of food, leading to its accumulation in fatty tissue in animals and humans. The elimination half-life of dioxin in humans (7-10 years) may favor the potentially continuous and long-lasting activation of AhR, leading to perpetual immune suppression and facilitating the onset, growth, and diffusion of tumors, especially in young people. In the cancer immunoediting hypothesis, which subdivides the relationship between tumor and immune system into three phases: elimination, equilibrium, and escape, it is thought that dioxin accumulation may cause an inevitable shift toward tumor escape. [ABSTRACT FROM AUTHOR]

Abstract: The concept of cancer immunotherapy stems from the proposed function of the immune system, called immunosurveillance, to protect against growing tumors. Due to genetic aberrations, tumor cells display an altered repertoire of MHC-associated peptides that can lead to the activation of immune cells able to eliminate the transformed cells. In some instances, under the pressure of the immune system, both the tumor and its microenvironment are shaped and immune-resistant tumor variants are selected initiating the process of cancer immunoediting. This can impair not only host-generated immunosurveillance, but also attempts to harness the immune response for therapeutic purposes, namely immunotherapy. Rather than being an exhaustive review of the different approaches of cancer immunotherapy, the focus of this review is to provide the reader with future challenges of the field by proposing ‘second generation’ immunotherapy approaches that take into account immunosubversive mechanisms adopted by tumor cells. After an introduction on the process of immunosurveillance and immunoescape we will analyze why current immunotherapy approaches have not fulfilled their promise and will finish by summarizing what are the challenges for future approaches. [Copyright &y& Elsevier]

Over the last 12 yr, we have shown that interferony and lymphocytes collaborate to regulate tumor development in mice. Specifically, we found that the immune system not only prevents the growth of primary (carcinogen-induced and spontaneous) and transplanted tumors but also sculpts the immunogenicity of tumors that form. These observations led us to refine the old and controversial “cancer immuno-surveillance” hypothesis of Burnet and Thomas into one that we termed cancer immunoediting that better emphasizes the paradoxical host-protective and tumor-sculpting roles of immunity on developing tumors. Our current work focuses on defining the molecular mechanisms that underlie cancer immunoediting and exploring the implications of this process for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Interferon-gamma (IFNγ) is a cytokine that plays physiologically important roles in promoting innate and adaptive immune responses. The absence of IFNγ production or cellular responsiveness in humans and experimental animals significantly predisposes the host to microbial infection, a result that validates the physiologic importance of this cytokine in preventing infectious disease. Recently, an additional role for IFNγ in preventing development of primary and transplanted tumors has been identified. Although there now appears to be a consensus that IFNγ promotes host responses to tumors, the mechanisms by which this cytokine achieves its effects remain unclear. In this review, we briefly discuss key issues of the molecular cell biology of IFNγ and its receptor that are most relevant to IFNγ-dependent anti-tumor effects and then focus on the data implicating IFNγ as a critical immune system component that regulates tumor development. Potential mechanisms underlying IFNγ’s anti-tumor effects are discussed and a preliminary integrative model of IFNγ’s actions on tumors is proposed. Finally, the capacity of IFNγ and lymphocytes to not only provide protection against tumor development but also to sculpt the immunogenic phenotype of tumors that develop in an immunocompetent host is presented and introduced as a “cancer immunoediting” process. [ABSTRACT FROM AUTHOR]