Mathematical modeling predicts optimal immune checkpoint inhibitor and radiotherapy combinations and timing of administration.

Radiotherapy (RT) combined with immune checkpoint inhibitor (ICI) therapy has attracted substantial attention due to its potential to improve outcomes for patients with several types of cancer. However, the optimal administration timepoints and drug combinations remain unclear because the mechanisms underlying RT-induced changes in immune checkpoint molecule expression and interaction with their ligand(s) remain unclear. Herein, we demonstrated the dynamics of lymphocyte-mediated molecular interactions in tissue samples from esophageal cancer patients throughout RT schedules.

The C5a/C5aR1 axis promotes migration of tolerogenic dendritic cells to lymph nodes, impairing the anticancer immune response.

The precise mechanisms by which the complement system contributes to the establishment of an immunosuppressive tumor microenvironment (TME) and promotes tumor progression remain unclear. In this study, we investigated the expression and function of complement C5a receptor 1 (C5aR1) in human and mouse cancer-associated dendritic cells (DCs). First, we observed an overexpression of C5aR1 in tumor-infiltrating DCs, compared to DCs from blood or spleen.

Tertiary lymphoid structures in pancreatic cancer are structurally homologous, share gene expression patterns and B-cell clones with secondary lymphoid organs but show increased T-cell activation.

Tertiary lymphoid structures (TLS) in cancer are considered ectopic hotspots for immune activation that are similar to lymphoid follicles in secondary lymphoid organs (SLO). This study elucidates shared and TLS/SLO-specific features in pancreatic ductal adenocarcinoma (PDAC). TLS abundance was related to superior survival and T-cell abundance in 110 treatment-naïve PDAC samples, underlining their clinical relevance.

Identification and phenotypic characterization of neoantigen-specific cytotoxic CD4+ T cells in endometrial cancer.

Tumor-reactive CD4+ T cells often accumulate in the tumor microenvironment (TME) in human cancer, but their functions and roles in antitumor responses remain elusive. Here, we investigated the immunopeptidome of HLA class II-positive (HLA-II+) endometrial cancer with an inflamed TME using a proteogenomic approach. We identified HLA-II neoantigens, one of which induced polyclonal CD4+ tumor-infiltrating lymphocyte (TIL) responses.

Natural killer cell-mediated cytotoxicity shapes the clonal evolution of B cell leukaemia.

The term cancer immunoediting describes the dual role by which the immune system can suppress and promote tumour growth and is divided into three phases: elimination, equilibrium and escape. The role of NK cells has mainly been attributed to the elimination phase. Here we show that NK cells play a role in all three phases of cancer immunoediting.

The HSP90 Inhibitor Pimitespib Targets Regulatory T Cells in the Tumor Microenvironment.

Regulatory T (Treg) cells play key roles in cancer immunity by suppressing a range of antitumor immune responses and contributing to resistance to programmed death (PD)-1 blockade therapy. Given their critical roles in self-tolerance, local control of immunosuppression by Treg cells, such as in the tumor microenvironment (TME), has been intensively studied. Inhibition of heat shock protein 90 (HSP90), a chaperone with vital roles in regulating proteostasis in cancer cells, impedes cancer progression by interrupting oncogenic signaling pathways and potentially modulating antitumor immunity, but we have very little mechanistic insight into these immune modulatory effects.

Blocking WNT7A Enhances MHC-I Antigen Presentation and Enhances the Effectiveness of Immune Checkpoint Blockade Therapy.

The limited infiltration of CD8+ T cells in tumors hampers the effectiveness of T cell-based immunotherapy, yet the mechanisms that limit tumor infiltration by CD8+ T cells remain unclear. Through bulk RNA sequencing of human tumors, we identified a strong correlation between WNT7A expression and reduced CD8+ T-cell infiltration. Further investigation demonstrated that inhibiting WNT7A substantially enhanced MHC-I expression on tumor cells.

Setdb1-loss induces type-I interferons and immune clearance of melanoma.

Despite recent advances in the treatment of melanoma, many patients with metastatic disease still succumb to their disease. To identify tumor-intrinsic modulators of immunity to melanoma, we performed a whole-genome CRISPR screen in melanoma and identified Setdb1 as well as all components of the HUSH complex. We found that loss of Setdb1 leads to increased immunogenicity and complete tumor clearance in a CD8+ T-cell dependent manner.

CD49a targeting enhances NK cell function and antitumor immunity.

Approximately 70% of patients receiving immune checkpoint blockade therapies develop treatment resistance. Thus, there is a need for the identification of additional immunotherapeutic targets. CD49a is a membrane protein expressed on NK cells and T cells.

A PSMA-targeted Tri-specific Killer Engager enhances NK cell cytotoxicity against prostate cancer.

Natural killer (NK) cell tumor infiltration is associated with good prognosis in patients with metastatic castration-resistant prostate cancer (mCRPC). NK cells recognize and kill targets by a process called natural cytotoxicity. We hypothesized that promoting an antigen-specific synapse with co-activation may enhance NK cell function in mCRPC.

Targeting of tumoral NAC1 mitigates myeloid-derived suppressor cell-mediated immunosuppression and potentiates anti-PD-1 therapy in ovarian cancer.

Epithelial ovarian cancer (EOC) is the most common type of ovarian cancer with a low rate of response to immunotherapy such as immune checkpoint blockade (ICB) therapy. Here, we report that nucleus accumbens-associated protein 1 (NAC1), a putative driver of EOC, has a critical role in immune evasion. We showed in murine ovarian cancer models that depleting or inhibiting tumoral NAC1 reduced the recruitment and immunosuppressive function of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME), led to significant increases of cytotoxic tumor-infiltrating CD8+ T cells, and promoted antitumor immunity and suppressed tumor progression.

Inflammatory stress determines the need for chemotherapy in patients with HER2-positive esophagogastric adenocarcinoma receiving targeted and immunotherapy.

Anti-PD-1, trastuzumab, and chemotherapy are used in the treatment of patients with advanced HER2-positive esophagogastric adenocarcinoma (EGA), but long-term survival remains limited. Herein, we report extended follow-up data from the INTEGA trial (NCT03409848), which investigated the efficacy of the anti-PD-1 nivolumab, trastuzumab, and FOLFOX chemotherapy (FOLFOX arm) in comparison to a chemotherapy-free regimen involving nivolumab, trastuzumab, and the anti-CTLA-4 ipilimumab (Ipi arm) in the first-line setting for advanced disease. The 12-month overall survival (OS) showed no statistical difference between the arms, with 57% OS (95% CI: 41%-71%) in the Ipi arm and 70% OS (95% CI: 54%-82%) in the FOLFOX arm.

Combination CXCR4 and PD1 blockade enhances intratumoral dendritic cell activation and immune responses against hepatocellular carcinoma.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of unresectable hepatocellular carcinoma (HCC), but their impressive efficacy is seen in just a fraction of patients. One key mechanism of immunotherapy resistance is the paucity of dendritic cells (DCs) in liver malignancies. Here, we tested combination blockade of programmed death receptor 1 (PD1) and CXCR4, a receptor for CXCL12, a pleiotropic factor that mediates immunosuppression in tumors.

Alternate MHC I antigen presentation pathways allow CD8+ T-cell recognition and killing of cancer cells in the absence of ß2M or TAP.

Major histocpmpatibilty complex class I (MHC I) antigen presentation allows CD8+ T cells to detect and eliminate cancerous or virally infected cells. The MHC I pathway is not essential for cell growth and viability and consequently cancers and viruses can evade control by CD8+ T cells by inactivating antigen presentation. In cancers, two common ways for this evasion are the loss of either the MHC I light chain (ß2M) or the cytosol-to-endoplasmic reticulum (ER) peptide transporter (TAP).

BTN2A1: A Novel Target to Boost Tumor Killing Capacity of Human γδ T Cells.

γδ T cells have recently raised great interest as effector cells in cancer immunotherapy because of their HLA-independent mode of action and their broad tumor reactivity. To translate the application of γδ T cells into clinically effective immunotherapies, specific tumor targeting and/or boosting of γδ T-cell activation in vivo seem to be a critical step. In this issue, Le Floch and colleagues report a new strategy for enabling γδ T cells to be specifically activated to kill acute lymphoblastic leukemia cells and solid tumor cells using agonistic BTN2A1 antibodies.

T cells Instruct Immune Checkpoint Inhibitor Therapy Resistance in Tumors Responsive to IL-1 and TNFα Inflammation.

Resistance to immune checkpoint inhibitors (ICIs) is common, even in tumors with T cell infiltration. We thus investigated consequences of ICI-induced T cell infiltration in the microenvironment of resistant tumors. T cells and neutrophil numbers increased in ICI-resistant tumors following treatment, in contrast to ICI-responsive tumors.

Preclinical development of T cells engineered to express a T cell antigen coupler (TAC) targeting Claudin 18.2-positive solid tumors.

The T cell antigen coupler (TAC) is a chimeric receptor that facilitates tumor antigen-specific activation of T cells by co-opting the endogenous T cell receptor complex in the absence of tonic signaling. Previous data demonstrates that TAC affords T cells with the ability to induce durable and safe anti-tumor responses in preclinical models of hematological and solid tumors. Here, we describe the preclinical pharmacology and safety of an autologous Claudin 18.

Level of expression of MHCI-presented neoepitopes influences tumor rejection by neoantigen-specific CD8+ T cells.

Neoantigen-targeted therapy holds an array of benefits for cancer immunotherapy, but the identification of peptide targets with tumor rejection capacity remains a limitation. To better define the criteria dictating tumor rejection potential, we examined the capacity of high-magnitude T cell responses induced towards several distinct neoantigen targets to regress MC38 tumors. Surprisingly, despite their demonstrated immunogenicity, vaccine-induced T-cell responses were unable to regress established MC38 tumors or prevent tumor engraftment in a prophylactic setting.

Transient EZH2 suppression by Tazemetostat during in vitro expansion maintains T-cell stemness and improves adoptive T-cell therapy.

The histone methyltransferase enhancer of zeste homolog 2 (EZH2) plays important roles in T-cell differentiation, proliferation and function. Previous studies have demonstrated that genetic deletion of EZH2 in CD8+ or total T cells impairs their antiviral and antitumor activity, cytokine production and ability to expand upon rechallenge. Contrary to the detrimental role of deleting T cell-intrinsic EZH2, here we have demonstrated that transient inhibition of EZH2 in T cells prior to the phenotypic onset of exhaustion with a clinically approved inhibitor, Tazemetostat, delayed their dysfunctional progression and preserved T-cell stemness and polyfunctionality but had no negative impact on cell proliferation.