Cancer immunology research最新文献

The immunosuppressive tumor microenvironment (TME) in glioblastoma (GBM) is predominantly shaped by tumor-associated macrophages (TAMs), yet the key chemokine axes driving immunosuppression and progression remain poorly defined. In this study, we identified the CCL1-AMFR axis as a critical contributor to GBM progression through dual immune-modulatory and tumor-intrinsic mechanisms. Analysis of human glioma datasets and tissue samples revealed that CCL1 - predominantly derived from TAMs - was significantly overexpressed in GBM and correlated with poor patient survival. Functionally, CCL1 recruited Arg1+ immunosuppressive macrophages in an AMFR-dependent manner. Myeloid-specific knockout of either Ccl1 or Amfr in murine models reduced TAM infiltration and extended survival. Although CCL1 can signal through both CCR8 and its recently identified receptor AMFR, AMFR played the dominant role in mediating CCL1-induced tumor cell proliferation and migration by activating the FAK and PI3K-AKT signaling pathways. Importantly, therapeutic neutralization of CCL1 using a monoclonal antibody significantly prolonged median survival in both immunocompetent GL261 murine GBM and BNI1-3 patient-derived xenograft (PDX) models, accompanied by reduced TAM infiltration and attenuated FAK/PI3K-AKT signaling. Our findings establish TAM-derived CCL1 as a pivotal regulator of GBM pathogenesis and demonstrate that targeting the CCL1-AMFR axis disrupts both tumor-intrinsic growth and immunosuppressive TME dynamics, representing a promising therapeutic strategy for this lethal malignancy.

Subcutaneous administration is an increasingly patient-preferred, alternative route of administration for monoclonal antibodies (mAb). To overcome the dose-volume restriction with subcutaneous administration and enable the large mAb doses typically required for immunotherapy, recombinant human hyaluronidase PH20 is co-dosed to transiently depolymerize hyaluronan at the injection site. Despite increasing clinical approvals and clinical trials of combination products with PH20, the potential impact of PH20 in facilitating intravenous-to-subcutaneous dose switching is largely unknown. In this study, we investigated whether increased lymphatic drainage via subcutaneous administration with PH20 co-dosing could improve the efficacy of anti-CTLA4 (αCTLA4) by increasing mAb access to the site of antitumor immunomodulation at the tumor-draining lymph node (TDLN). We showed that subcutaneous administration with PH20 significantly enhanced TDLN exposure of αCTLA4. In murine tumor models (CT26/HAS or MC38/OVA), this translated to improved tumor control compared with intravenous, and was either more efficacious or noninferior to subcutaneous alone. Greater efficacy occurred concomitantly with increased cytotoxic effector CD8+ T cells in the tumor and CD62L+ stem-like CD8+ T cells in the TDLN. This was due to increased mAb access to CTLA4+ T-cell populations at the TDLN and was only preserved at a lower mAb dose after subcutaneous administration with PH20. The efficacy advantage of subcutaneous administration with PH20 was primarily apparent for TDLN-targeted mAb (αCTLA4), as combination therapy with a non-TDLN-targeted mAb (αTIM3) was similarly efficacious regardless of dose routes. Overall, our study highlights the potential utility of PH20 to improve TDLN-targeted immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, with liver metastases significantly worsening outcomes. However, features of the tumor microenvironment (TME) that are distinct between primary and metastatic sites remain poorly defined. Cellular neighborhoods within the TME are recognized as functional units that influence tumor behavior. Conventional spatial methods, which assign equal weights to all cells in a region, fail to capture the nuances of cellular interactions. To address this, we report here the development of Functional Cellular Neighborhood (FunCN) quantification, which integrates both the proportion and proximity of surrounding cells. Applying FunCN to PDAC imaging mass cytometry data, we identified neutrophil-enriched interactions in liver metastases compared to primary tumors, correlating with elevated VISTA expression by tumor cells. Additionally, FunCN clusters around CD8⁺ T cells in pancreas and liver were associated with higher TIGIT and LAG3, respectively. These findings demonstrate the importance of spatial immune landscapes in PDAC and identify potential therapeutic opportunities.

Chimeric antigen receptor (CAR) T-cell therapy enriched for a memory-like phenotype may persist and function longer than a non-enriched product, thereby improving duration of response (DOR). We conducted a phase 1 study with bb21217 (NCT03274219), an anti-B-cell maturation antigen CAR T-cell therapy manufactured in the presence of bb007 (phosphoinositide 3-kinase inhibitor) to enrich for T cells with a memory-like phenotype, in patients with relapsed/refractory multiple myeloma (N=72). No new safety concerns were raised with bb21217 therapy (three cases each of grade ≥3 CRS and grade ≥3 neurotoxicity were observed). The objective response rate was 69.4% and median DOR was 23.8 (95% confidence interval, 16.8-34.8) months. Analysis of drug product established an association between early memory phenotype and robust expansion and depth of response. Examination of baseline characteristics indicated that tumor burden and prior therapies influenced DOR. The generation of CAR T cells early in a disease course when tumor burden is lower and source material exhibits a more naïve phenotype may maximize the clinical benefit potential of the drug product.

Lung cancer is the leading cause of cancer-related deaths worldwide and, despite advances in treatment, immune suppression remains an obstacle to effective therapy. Effector CD4+ T cells (CD4+ Teffs) are critical for antitumor immunity, but their function is often inhibited by regulatory T cells (Tregs), which accumulate in lung tumors and mediate suppressive functions through multiple mechanisms. This suppression leads to tumor progression and poor patient outcomes. However, the mechanisms underlying Treg-mediated suppression are not fully understood. Herein, we identify the extracellular ATP receptor P2RX7 as a key regulator of Treg function in lung tumors. In a murine lung cancer model induced by Lewis lung carcinoma cells, we found that P2RX7 enhanced the suppressive capacity of tumor-infiltrating Tregs, promoting tumor growth. In T cell-specific P2RX7-KO mice, reduced Treg infiltration was accompanied by increased CD4+ Teff accumulation and improved tumor control. Treg-specific P2RX7-KO mice exhibited reduced tumor growth, confirming a Treg-intrinsic role of P2RX7. Suppression assays revealed that tumor-infiltrating wild-type Tregs had greater suppressive activity compared to P2RX7-KO Tregs, which failed to inhibit type 1 and Tfh-like responses. This was associated with increased tumor-specific IgG production by lung B cells in P2RX7-KO mice. We also observed that wild-type Tregs expressed higher levels of the immunosuppressive molecule CTLA-4 when compared to P2RX7-KO Tregs. Thus, we conclude that P2RX7 expression on Tregs is essential for their suppressive function in lung cancer and targeting of P2RX7 may constitute a strategy to improve lung cancer treatment by alleviating Treg-mediated immune suppression.

Identifying new therapeutic approaches in high-grade serous ovarian cancer (HGSC) requires the development of more accurate preclinical models that replicate the patient-specific tumor and its microenvironment. To address this, we established immunocompetent patient-derived cultures (iPDCs) for HGSC, cultured on a physiologically relevant human omentum-gel matrix. We developed a high-throughput platform that combines drug testing, histological analysis, genomic profiling, single-cell studies, and spatial biomarker discovery. Our results from 47 tumors showed that iPDCs recapitulated the tumor genomic and histological characteristics, while also retaining the intratumoral immune cells. The iPDC treatment responses correlated significantly with the patients' clinical treatment responses. Using iPDCs and scRNAseq, we identified potentially effective therapeutic options for patients with recurrent HGSC linked to distinct tumor cell states and mechanisms of resistance. High-throughput drug response profiling with single cell-imaging identified ataxia telangiectasia and Rad3-related inhibitor (ATRi) combined with an immunotherapy targeting Autotaxin as a promising new combination treatment for HGSC. Using hyperplexed imaging and the spatial analysis, we discovered that ATRi responses were associated with significant increases in both intra- and peritumoral T cell infiltration, particularly in PD1+ CD8+ T cells. Additionally, the ATRi induced reactivation of CD8+ T cells was linked to spatial interactions with replication stress positive tumor cells. Thus, our iPDC platform presents as a representative high-throughput ex vivo model to advance precision oncology in HGSC uncovering ATRi-immunotherapy combination as a potentially effective therapeutic option for clinical translation.

GPR84 is a medium-chain free fatty acid receptor predominantly expressed in myeloid cells. Previous studies have identified GPR84 as an enhancer of the pro-inflammatory myeloid cell responses and a regulator of metabolic homeostasis. However, the role of GPR84 in T cell function and metabolism remains largely unexplored. This study tested the effect of GPR84 modulation on CD8+ T cell function and metabolism in vitro and examined its effect on antitumor function in adoptive cellular therapy models. Pharmacological antagonism with GLPG1205 or genetic deletion of GPR84 promoted T cell differentiation, proliferation, cytokine production, and cytotoxicity, whereas agonism with DL175 reduced these functions. These functional changes were paralleled by changes in metabolic activity. Antagonism and genetic deletion increased glucose uptake, glycolysis, oxidative phosphorylation, and ATP production, which enhanced the overall cell energetic fitness, whereas agonism resulted in a quiescent energetic profile. Furthermore, antagonism or deletion of GPR84 in antigen-specific CD8+ T cells in adoptive cellular therapy models enhanced their antitumor effects in vivo. Thus, GPR84 inhibition improves CD8+ T cell function and may further enhance adoptive cellular therapies.

Tumor-associated macrophages (TAMs) represent the main immune population infiltrating cancers, and their abundance is generally correlated with a poor prognosis. The acquisition of protumor properties by TAMs involves several mechanisms, including expression of immunosuppressive enzymes. In this study, we explored the role of the enzyme IL-4 induced gene 1 (IL4I1) expressed by TAMs in murine models of melanoma. We found that IL4I1 expression was increased in subsets of TAMs during spontaneous melanoma progression and this increase could be blocked by TNF-α, IL-12, and IL-1β co-neutralization. Macrophage-specific IL4I1 deletion delayed tumor onset and metastatic dissemination. Mechanistically, targeting IL4I1 restored antitumor functions of TAMs with increased antigen-presenting capacity and restored the proliferative and cytotoxic capacities of CD8+ T cells. Chemical blockade of IL4I1 partially reproduced these results. Overall, we demonstrate the key role of IL4I1 in TAM-mediated immune escape of melanoma. As most human tumors contain TAMs expressing IL4I1, our results may have implications for cancer immunotherapy.

Combination vaccine and checkpoint inhibitor therapy has previously demonstrated immunologic responses in patients with pancreatic ductal adenocarcinoma (PDAC), although with limited efficacy. An urgent need to augment responses has warranted a deeper understanding of how each treatment modality contributes to the overall inflammatory response. Serial blood samples from PDAC patients treated with GVAX, CRS-207, anti-CTLA-4, and/or anti-PD-1 therapies were profiled using two mass cytometry panels. Generating 260 cytometric profiles from 64 unique patients allowed us to create an annotated PDAC immunotherapy atlas. Analysis of this atlas revealed that while GVAX alone did not significantly alter T-cell relative frequencies, it induced T-cell activation and upregulated checkpoint expression. Adding anti-PD-1 blockade to GVAX further enhanced T-cell activation, whereas adding anti-CTLA-4 distinctly enhanced memory formation. Vaccine-mediated effects were similar, but GVAX promoted plasmacytoid dendritic cells more than CRS-207. Derived phenotypic patterns could also be projected onto tumor imaging data, underscoring the potential for discoveries relating treatment-induced peripheral signatures to changes in the tumor microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal and has poor immunogenicity, warranting the use of vaccines to guide and recruit the immune response. Building on prior efforts to achieve clinical immunotherapeutic responses against PDAC, we conducted a phase II study (NCT03190265) that combined attenuated mesothelin-secreting listeria vaccine (CRS-207) and GM-CSF-secreting allogeneic whole-cell vaccine (GVAX) along with checkpoint inhibition. Patients with metastatic PDAC who progressed on chemotherapy were enrolled in one of two treatment arms in a randomized fashion. CRS-207 was given with anti-PD1 (nivolumab) and anti-CTLA4 (ipilimumab) with (Arm A) or without (Arm B) GVAX. Primary endpoint was objective response rate (ORR) and the secondary endpoint was safety. 57 patients received at least one dose of treatment, with 2 partial responses (4% ORR), both Arm B. The response rates were not significantly different between the two arms. Related grade ≥3 adverse events were seen in 39 (68%) patients, including 33 events attributed to CRS-207. Mass cytometry analysis of serially obtained biospecimens demonstrated treatment-induced promotion of T-cell memory and infiltration into the tumor microenvironment (TME). Peptide-specific T-cell expansions in vitro followed by T-cell receptor sequencing revealed clones specific to mesothelin and mutant KRAS within the tumor. Accompanying these antitumor T-cell responses was significant enrichment of myeloid cells. High myeloid and Treg signatures correlated with poor responses. We conclude that GVAX/CRS-207 plus nivolumab and ipilimumab successfully generates and expands T-cell clones specific to mesothelin and mutant KRAS within the PDAC TME but immunotherapy-induced myeloid-cell enrichment remains a barrier to greater efficacy.