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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]

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]

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]

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]

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]

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]

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]