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Background: Tumors rewire their metabolism to achieve robust anabolism and resistance against therapeutic interventions like cisplatin treatment. For example, a prolonged exposure to cisplatin causes downregulation of pyridoxal kinase (PDXK), the enzyme that generates the active vitamin B6, and upregulation of poly ADP-ribose (PAR) polymerase-1 (PARP1) activity that requires a supply of nicotinamide (vitamin B3) adenine dinucleotide. We investigated the impact of the levels of PDXK and PAR on the local immunosurveillance (ie, density of the antigen presenting cells and adaptive immune response by CD8 T lymphocytes) in two different tumor types., Methods: Tumors from patients with locally advanced cervical carcinoma (LACC) and non-small cell lung cancer (NSCLC) were stained for PAR, PDXK, dendritic cell lysosomal associated membrane glycoprotein (DC-LAMP) and CD8 T cell infiltration. Their correlations and prognostic impact were assessed. Cisplatin-resistant NSCLC cell clones isolated from Lewis-lung cancer (LLC) cells were evaluated for PAR levels by immunoblot. Parental (PAR low ) and cisplatin-resistant (PAR high ) clones were subcutaneously injected into the flank of C57BL/6 mice. Tumors were harvested to evaluate their immune infiltration by flow cytometry., Results: The infiltration of tumors by CD8 T and DC-LAMP + cells was associated with a favorable overall survival in patients with LACC (p=0.006 and p=0.008, respectively) and NSCLC (p<0.001 for both CD8 T and DC-LAMP cells). We observed a positive correlation between PDXK expression and the infiltration by DC-LAMP (R=0.44, p=0.02 in LACC, R=0.14, p=0.057 in NSCLC), and a negative correlation between PAR levels and CD8 T lymphocytes (R=-0.39, p=0.034 in LACC, R=-0.18, p=0.017 in NSCLC). PARP1 is constitutively hyperactivated in cisplatin-resistant LLC cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PAR high ). Tumors formed by such cancer cells injected into immunocompetent mice were scarcely infiltrated by CD8 T (p=0.028) and antigen presenting cells (p=0.086)., Conclusions: Oncometabolic features can impact local immunosurveillance, providing new functional links between cisplatin resistance and therapeutic failure., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Natural killer (NK) cells play a crucial role in tumor immunosurveillance through their cytotoxic effector functions and their capacity to interact with other immune cells to build a coordinated antitumor immune response. Emerging data reveal NK cell dysfunction within the tumor microenvironment (TME) through checkpoint inhibitory molecules associated with a regulatory phenotype., Objective: We aimed at analyzing the gene expression profile of intratumoral NK cells compared with non-tumorous NK cells, and to characterize their inhibitory function in the TME., Methods: NK cells were sorted from human lung tumor tissue and compared with non- tumoral distant lungs., Results: In the current study, we identify a unique gene signature of NK cell dysfunction in human non-small cell lung carcinoma (NSCLC). First, transcriptomic analysis reveals significant changes related to migratory pattern with a downregulation of sphingosine-1-phosphate receptor 1 (S1PR1) and CX3C chemokine receptor 1 (CX3CR1) and overexpression of C-X-C chemokine receptor type 5 (CXCR5) and C-X-C chemokine receptor type 6 (CXCR6). Second, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and killer cell lectin like receptor (KLRC1) inhibitory molecules were increased in intratumoral NK cells, and CTLA-4 blockade could partially restore MHC class II level on dendritic cell (DC) that was impaired during the DCs/NK cell cross talk. Finally, NK cell density impacts the positive prognostic value of CD8 + T cells in NSCLC., Conclusions: These findings demonstrate novel molecular cues associated with NK cell inhibitory functions in NSCLC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immune checkpoint inhibitors are monoclonal antibodies indicated for an increasing number of malignant diseases. These agents can cause specific side effects, which need to be anticipated while clear patterns of management need to be established. Immune checkpoint inhibitor-mediated gastrointestinal side effects, including diarrhea and colitis, occur in up to 30% of patients. Severe colitis can lead to severe dehydration or intestinal perforation. Endoscopic lesions and histopathological features of immune checkpoint inhibitor-induced colitis are similar to an inflammatory bowel disease (IBD) flare. Patients with immune checkpoint inhibitor-induced diarrhea and colitis are treated with corticosteroids. Infliximab can be used in cases of corticosteroid failure. Rectosigmoïdoscopy or colonoscopy should be performed when severe immune checkpoint inhibitor-induced colitis is suspected, but endoscopic investigations should not delay treatment. Specific patient education as well as co-operation between oncologists and gastroenterologists is essential.

Immune-checkpoint inhibitors represent potent new therapies for most lymphomas, particularly for refractory diseases. Contrasting with solid tumors the majority of lymphoma are sensitive to conventional therapies and immunotherapies such as anti-CD20 or anti-CD30. But relapsing lymphoma or refractory disease have a very poor prognosis and new drugs are mandatory. Immune-checkpoint inhibitors targeting CTLA4, PD-1 et PD-L1 demonstrated efficiency with prolonged survivals even after bone marrow allograft for aggressive disease. Lymphomas differ from solid tumors as tumor cells belong to the immune compartment and therefore molecules targeting immune cells may act on both immune environment and tumor cells. Furthermore, PD-L1 expression in most lymphomas is related to tumor cell molecular alterations such as PD-L1 gene amplification or mutation. PD-L1 protein expression on tumor cells and immune cells, particularly it frequency and distribution vary according to different lymphoma subtype and it may help to assess diagnosis as it may predict therapeutical response., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background: Few data have been published on the clinical and histopathological characteristics of advanced non-small–cell lung cancer (NSCLC) patients with high PD-L1 expression versus intermediate or none and the prognostic value of PD-L1 expression for patients treated with chemotherapy is unknown. This study was undertaken to prospectively assess the prognostic value of tumor-cell (TC) and immune-cell (IC) PD-L1 expressions for advanced NSCLC patients. Methods: It was a prospective, multicenter study on advanced NSCLC patients, with performance status 0/1, scheduled, consecutively, to receive first-line platin-based chemotherapy. PD-L1 expression was determined immunochemically (Dako Autostainer and monoclonal antibody 22C3) and its impact on progression-free survival (PFS) and overall survival (OS) assessed. Results: Among 198 patients screened in 19 centers, 140 were included median age: 66.5 ± 10 years; 76.4% men; 79.3% Caucasians; 10.7% nonsmokers; 63.6% adenocarcinomas; < 1%, 1– 50% and ≥ 50% TC PD-L1–expression rates were 47.1%, 25.7% and 27.2% of patients, respectively; respective null, intermediate and high rates on ICs were 35.7%, 38.6% and 25.7%. Second- and third-line chemotherapies were administered to 58.6% and 26.4% of the patients, respectively. None received immunotherapy. First-, second- and third-line median (95% CI) PFS lasted 4.6 (3.6– 5.2), 3.7 (2.3– 4.7) and 2.2 (1.5– 4.3) months, respectively; median OS was 16.9 (11.4– 19.9) months. No significant PFS and OS differences were observed according to TC or IC PD-L1 expression. Conclusion: According to the results of this prospective, multicenter study, neither TC nor IC PD-L1 expression appears to be prognostic for chemotherapy-managed advanced NSCLC patients. [ABSTRACT FROM AUTHOR]

Solid tumors, beyond mere accumulation of cancer cells, form a complex ecosystem consisting of normal epithelial cells, fibroblasts, blood and lymphatic vessels, structural components, and infiltrating hematopoietic cells including myeloid and lymphoid elements that impact tumor growth, tumor spreading, and clinical outcome. The composition of the immune microenvironment is diverse, including various populations of T cells, B cells, dendritic cells, natural killer cells, myeloid-derived suppressor cells, neutrophils, or macrophages. The immune contexture describes the density, location, and organization of these immune cells within solid tumors. In lung cancer, which is the deadliest type of cancer, and particularly in non-small cell lung cancer, its most prevalent form, reports have described some of the interactions between the tumor and the host. These data, in addition to articles on various types of tumors, provide a greater understanding of the tumor-host microenvironment interaction and stimulate the development of prognostic and predictive biomarkers, the identification of novel target antigens for therapeutic intervention, and the implementation of tools for long-term management of patients with cancer. [ABSTRACT FROM AUTHOR]

Although immune checkpoint inhibitors have shown improvement in survival in comparison to chemotherapy in urothelial bladder cancer, many patients still fail to respond to these treatments and actual efforts are made to identify predictive factors of response to immunotherapy. Understanding the tumor-intrinsic molecular basis, like oncogenic pathways conditioning the presence or absence of tumor-infiltrating T cells (TILs), should provide a new rationale for improved anti-tumor immune therapies. In this study, we found that urothelial bladder cancer from human samples bearing PIK3CA gene mutations was significantly associated with lower expression of a defined immune gene signature, compared to unmutated ones. We identified a reduced 10-gene immune gene signature that discriminates muscle-invasive bladder cancer (MIBC) samples according to immune infiltration and PIK3CA mutation. Using a humanized mouse model, we observed that BKM120, a pan-PI3K inhibitor, significantly inhibited the growth of a human bladder cancer cell line bearing a PIK3CA mutation, associated to increased immune cell infiltration (hCD45+). Using qRT-PCR, we also found an increase in the expression of chemokines and immune genes in PIK3CA-mutated tumors from mice treated with BKM120, reflecting an active immune infiltrate in comparison to untreated ones. Moreover, the addition of BKM120 rendered PIK3CA-mutated tumors sensitive to PD-1 blockade. Our results provide a relevant rationale for combination strategies of PI3K inhibitors with immune checkpoint inhibitors to overcome resistance to immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Co-stimulatory and inhibitory receptors expressed by immune cells in the tumor microenvironment modulate the immune response and cancer progression. Their expression and regulation are still not fully characterized and a better understanding of these mechanisms is needed to improve current immunotherapies. Our previous work has identified a novel ligand/receptor pair, LLT1/CD161, that modulates immune responses. Here, we extensively characterize its expression in non-small cell lung cancer (NSCLC). We show that LLT1 expression is restricted to germinal center (GC) B cells within tertiary lymphoid structures (TLS), representing a new hallmark of the presence of active TLS in the tumor microenvironment. CD161-expressing immune cells are found at the vicinity of these structures, with a global enrichment of NSCLC tumors in CD161+ CD4+ and CD8+ T cells as compared to normal distant lung and peripheral blood. CD161+ CD4+ T cells are more activated and produce Th1-cytokines at a higher frequency than their matched CD161-negative counterparts. Interestingly, CD161+ CD4+ T cells highly express OX40 co-stimulatory receptor, less frequently 4-1BB, and display an activated but not completely exhausted PD-1-positive Tim-3-negative phenotype. Finally, a meta-analysis revealed a positive association of CLEC2D (coding for LLT1) and KLRB1 (coding for CD161) gene expression with favorable outcome in NSCLC, independently of the size of T and B cell infiltrates. These data are consistent with a positive impact of LLT1/CD161 on NSCLC patient survival, and make CD161-expressing CD4+ T cells ideal candidates for efficient anti-tumor recall responses. [ABSTRACT FROM AUTHOR]

• Loss of BRG1/SMARCA4-deficient carcinoma is found in 5–10% of NSCLC. • SMARCA4-deficient lung carcinomas are associated with poor clinical outcome. • SMARCA4-deficient carcinomas are highly infiltrated in FOXP3+ cells and neutrophils. • Non-response to anti-PD1 could be related to the immunosuppressive tumor environment. SMARCA4/BRG1 loss of expression occurs in 5–10% of non-small cell lung carcinomas (NSCLC). We investigated the pathological, molecular and immune environment characteristics of this deficiency among NSCLC, its impact on overall survival (OS) of resected patients and the sensitivity to anti-PD1 inhibitors in metastatic patients. BRG1 expression was assessed by immunohistochemistry to identify SMARCA4-deficient NSCLC (SD-NSCLC) from the cancer tissue collection of Cochin Hospital (Paris, France). Molecular profiles were analyzed by targeted NGS covering 28 genes in 63 resected SD-NSCLC. The balance of immune cells between CD8+, FOXP3+ cells and neutrophils (CD66b+) was characterized by multiplex immunohistochemistry and compared to non-SD NSCLC. Clinical outcome after anti–PD-1 therapy was evaluated in 7 SD-NSCLC out of 77 NSCLC patients. SD-NSCLCs were more commonly found in TTF1-negative high-grade adenocarcinomas and pleomorphic carcinomas. They were associated with few targetable alterations (KRAS G12C and MET amplification). Their immune environment was characterized by an increased of FOXP3+ cell and neutrophil densities, but not of CD8+ T cells, compared to non-SD NSCLC. SD-NSCLC patients had a significantly shorter OS in early stages of resected patients and in metastatic patients treated by anti-PD1 treatment. BRG1-loss in NSCLC confers a poor prognosis and is associated with an immunosuppressive environment that could be responsible of limited efficacy to anti-PD1 inhibitors. The identification of SD-NSCLC by BRG1 immunohistochemistry is desirable for an optimal management of NSCLC patients. [ABSTRACT FROM AUTHOR]

De novo formation of tertiary lymphoid structures (TLS) has been described in lung cancers. Intratumoral TLS seem to be functional and are associated with a long-term survival for lung cancer patients, suggesting that they epresent an activation site for tumor-specific T cells. Here, we characterized T-cell recruitment to TLS in human lung cancer to identify the adhesion molecules and chemoattractants orchestrating this migration. We found hat most TLS T cells were CD62L+ and mainly of CD4+ memory phenotype, but naive T cells were highly enriched in these structures as compared with the rest of the tumor. A specific gene expression signature associated with T cell presence was identified in TLS, which included chemokines (CCL19, CCL21, CXCL13, CCL17, CCL22, and IL16), adhesion molecules (ICAM-2, ICAM-3, VCAM-1, and MAdCAM-1) and integrins alphaL, alpha4, and alphaD). The presence of the corresponding receptors on TLS T cells was confirmed. ntratumoral PNAd+ high endothelial venules also were exclusively associated with TLS and colocalized with CD62L+ lymphocytes. Together, these data bring new insights into the T-cell recruitment to intratumoral TLS and suggest that blood T cell enter into TLS via high endothelial venules, which represent a new gateway for T cells to the tumor. Findings identify the molecules that mediate migration of tumor-specific T cells into TLS where T cell priming occurs, suggesting new strategies to enhance the efficacy of cancer immunotherapies. [ABSTRACT FROM AUTHOR]

Long-term efficacy of anti-PD1 therapy and the need for a consolidation with allogenic haematopoietic stem cell transplantation (allo-HSCT) remain unclear in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL). We retrospectively analysed 78 patients with R/R HL treated with nivolumab in the French Early Access Program and compared their outcomes according to subsequent allo-HSCT. After a median follow-up of 34.3 months, the best overall response rate was 65.8%, including 38.2% complete responses (CRs). The median progression-free survival (PFS) was 12.1 months. Patients reaching a CR upon nivolumab had a significantly longer PFS than those reaching a partial response (PR) (median = not reached vs 9.3 months, p < 0.001). In our cohort, 13 patients who responded (i.e. in CR or PR) to nivolumab monotherapy underwent consolidation with allo-HSCT. Among responding patients, none of those who underwent subsequent allo-HSCT (N = 13) relapsed, whereas 62.2% of those who were not consolidated with allo-HSCT (N = 37) relapsed (p < 0.001). There was no difference in overall survival (OS) between the two groups. Five of 6 patients who were not in CR at the time of transplantation (4 PRs and 1 progressive disease) converted into a CR after allo-HSCT. Most patients with R/R HL treated with anti-PD1 monotherapy eventually progressed, notably those who did not achieve a CR. Patients undergoing consolidation with allo-HSCT after anti-PD1 therapy experienced prolonged disease-free survival compared with non-transplanted patients, but this difference did not translate into a benefit in OS. This information should be considered when evaluating the risk/benefit ratio of allo-HSCT after anti-PD1 therapy. • Most patients with relapsed/refractory Hodgkin lymphoma eventually progressed during anti-programmed cell death-1 (anti-PD1) therapy. • In responding patients, the relapse rate was lower in patients consolidated with allogenic haematopoietic stem cell transplantation (allo-HSCT). • Among responders, subsequent allo-HSCT was not associated with a greater overall survival. [ABSTRACT FROM AUTHOR]

Introduction Pulmonary Sarcomatoid Carcinoma (PSC) is a rare subset of NSCLC, associated with worse prognosis and resistant to platinum-based regimens. Recent investigations have shown high levels of PD-L1 expression in PSC, providing a rationale for the potential use of immunotherapy. In this study, we investigated whether the PD-L1 expression was related to clinico-pathologic and molecular characteristics. Materials and methods Fortythree surgically-resected PSCs were selected from 2006 to 2014 and clinical information retrieved. PD-L1 expression was analyzed by immunohistochemistry and correlated with the clinic-pathologic features and driver gene mutations analyzed by Next-Generation-Sequencing. Correlation of clinical, pathological and genetic variants with PD-L1 expression positivity were tested by Fisher’s exact test analysis. Results About 25% of PSCs showed a significant expression of PD-L1 (positive staining defined as staining in ≥10% of tumor cells). PD-L1 expression was associated with aggressive pathological features of PSCs including N2-involvement (PD-L1 positive in 83.3% of N2-PSCs vs in 16.2% of N0/N1-PSCs, p = 0.003) and presence of either local (p = 0.038) and distant metastases (p = 0.022). Furthermore, PD-L1 expression was significantly associated with the overall mutational load of the tumors (PD-L1 positivity only in PSCs with at least one mutational event) and in particular with the presence of KRAS mutation (PD-L1 positive in 44.4% of KRAS -Mut PSCs vs 12.0% in KRAS -Wild PSCs). The correlation between PD-L1 expression and KRAS -mutation were found at univariate analysis (p = 0.031), even considering PD-L1 as a continuous variable (p = 0.018), and confirmed at multivariate analysis (p = 0.035). The mutational status of the other genes explored in the NGS-panel ( EGFR, APC, PTEN, PIK3CA, TP53 and STK11) did not correlate with PD-L1 expression. Conclusions PD-L1 expression significantly correlates with overall mutational load and KRAS mutational status in pulmonary sarcomatoid carcinomas. [ABSTRACT FROM AUTHOR]