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Editorial on the Research Topic Towards a more faithful ex vivo modelling of tumor-immune-stroma communication In the past two decades of cancer research, the complexity of tumor microenvironments has gained increasingly appreciation, and a lot of effort has been put into developing models to study how host immune and stromal cells interact with a growing cancer. Notably, the review Gaebler et al. delved in the important role of microfluidic systems in advancing our understanding of the TME and presents current microfluidic model systems that aim to dissect tumor-stromal, tumor-immune and immune-stromal cellular interactions in various “cold” tumors. The development of continually-perfused multi-channel systems with comparable size to blood capillaries can help mimic the actual flux of nutrients, metabolites, and gases, provide a better fidelity to the spatiotemporal distribution of signaling molecules and cells and enable longitudinal studies in response to physiologically relevant biomechanical stimulation.

Tumor-associated fibrosis is characterized by unchecked pro-fibrotic and pro-inflammatory signaling. The components of fibrosis including significant numbers of cancer-associated fibroblasts, dense collagen deposition, and extracellular matrix stiffness, are well appreciated regulators of tumor progression but may also be critical regulators of immune surveillance. While this suggests that the efficacy of immunotherapy may be limited in highly fibrotic cancers like pancreas, it also suggests a therapeutic opportunity to target fibrosis in these tumor types to reawaken anti-tumor immunity. This review discusses the mechanisms by which fibrosis might subvert tumor immunity and how to overcome these mechanisms.

DeNardo and colleagues report that inhibiting focal adhesion kinase in pancreatic ductal adenocarcinoma (PDAC) in mice reduces fibrosis and improves the efficacy of tumor immunotherapy. These findings suggest an approach to overcome the immunosuppressive tumor microenvironment of PDAC. Single-agent immunotherapy has achieved limited clinical benefit to date in patients with pancreatic ductal adenocarcinoma (PDAC). This may be a result of the presence of a uniquely immunosuppressive tumor microenvironment (TME). Critical obstacles to immunotherapy in PDAC tumors include a high number of tumor-associated immunosuppressive cells and a uniquely desmoplastic stroma that functions as a barrier to T cell infiltration. We identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as an important regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlated with high levels of fibrosis and poor CD8 + cytotoxic T cell infiltration. Single-agent FAK inhibition using the selective FAK inhibitor VS-4718 substantially limited tumor progression, resulting in a doubling of survival in the p48-Cre ; LSL-Kras G12D ; Trp53 flox/+ (KPC) mouse model of human PDAC. This delay in tumor progression was associated with markedly reduced tumor fibrosis and decreased numbers of tumor-infiltrating immunosuppressive cells. We also found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to T cell immunotherapy and PD-1 antagonists. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and renders tumors responsive to immunotherapy.

Pancreatic ductal adenocarcinoma has a dismal prognosis. A comprehensive analysis of single-cell multi-omic data from matched tumour-infiltrated CD45+ cells and peripheral blood in 12 patients, and two published datasets, reveals a complex immune infiltrate. Patients have either a myeloid-enriched or adaptive-enriched tumour microenvironment. Adaptive immune cell-enriched is intrinsically linked with highly distinct B and T cell clonal selection, diversification, and differentiation. Using TCR data, we see the largest clonal expansions in CD8 effector memory, senescent cells, and highly activated regulatory T cells which are induced within the tumour from naïve cells. We identify pathways that potentially lead to a suppressive microenvironment, including investigational targets TIGIT/PVR and SIRPA/CD47. Analysis of patients from the APACT clinical trial shows that myeloid enrichment had a shorter overall survival compared to those with adaptive cell enrichment. Strategies for rationale therapeutic development in this disease include boosting of B cell responses, targeting immunosuppressive macrophages, and specific Treg cell depletion approaches. Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis involving evasion of immune control. Here, the authors perform a comprehensive analysis of single-cell multi-omic data revealing either a myeloid-enriched or adaptive-enriched tumour microenvironment, linked to distinct B and T cell clonal selection and differentiation, distinct overall survival, and potential therapeutic approaches.

Researchers at the Precision Immunology Institute at the Icahn School of Medicine (PrIISM), New York, describe their contribution to the global research effort against COVID-19 by trying to separate signal from noise in the preprint arena.This Comment article from the Precision Immunology Institute at the Icahn School of Medicine (PrIISM), New York, describes their efforts to provide critical reviews of COVID-19 articles posted daily on the preprint servers bioRxiv and medRxiv.

BackgroundAlthough colorectal cancer (CRC) is traditionally considered to be immunologically inert, some subsets of colorectal cancer, particularly mismatch repair-deficient (MMRd) tumors, can be highly responsive to immune checkpoint blockade (ICB). Recent studies show -that even mismatch repair-proficient (MMRp) tumors can respond to combined PD-1/CTLA-4 ICB. Tumor-associated macrophages (TAMs) are an influential component of the tumor microenvironment (TME), although the exact role of these immune cells in tumor pathogenesis and progression remains enigmatic. TAMs are highly heterogenous and can be either pro-inflammatory or anti-inflammatory, and thus exhibit anti-tumorigenic or pro-tumorigenic effects respectively. Signal regulatory protein α (SIRPα) is a transmembrane protein expressed on TAMs that binds to CD47 on target cells, eliciting a ‘don’t-eat-me’ signal that inhibits phagocytosis by macrophages. In preclinical studies, anti-SIRPα antibodies have been shown to induce macrophage-dependent anti-tumor activity and skew macrophages towards an anti-tumorigenic phenotype. Since colorectal cancer lesions are often dominated by both T cells and anti-inflammatory TAMs, combination therapy with an anti-SIRPα antibody and an anti-PD-1 antibody may result in synergistic killing of tumor cells by TAMs and T cells.MethodsThis phase I, open-label, parallel-cohort, single-center trial (NCT05446129) was designed to assess the safety, feasibility, clinical efficacy, and biological activity of BI-765063 (an anti-SIRPα antibody) in combination with either ezabenlimab (Cohort A) or pembrolizumab (Cohort B), both anti-PD-1 antibodies, in patients with early-stage, resectable CRC (figure 1). Each cohort will enroll 25 patients. Treatment will be given as a single-dose in the neoadjuvant setting. All patients will then be scheduled to undergo surgical resection 2 to 6 weeks after treatment administration. The primary endpoint is a composite safety and feasibility endpoint, defined as the proportion of patients exhibiting any grade-3 or higher treatment-related adverse event or any treatment-related adverse event delaying surgery more than 6 weeks after treatment administration. The secondary endpoints include pathological response, defined as 50% or greater tumor regression, time from treatment administration to surgery, and radiographic response. Tissue, blood, and stool will be collected prior to treatment administration and at the time of resection. Immune monitoring will be performed using multiplex and single-cell analysis platforms to define the immunodynamic effects of these therapies.Trial RegistrationClinicalTrials.gov Identifier: NCT05446129Ethics ApprovalOn 9/23/2022 an Institutional Review Board of the Mount Sinai School of Medicine, in accordance with Mount Sinai’s Federal Wide Assurances (FWA#00005656, FWA#00005651) to the Department of Health and Human Services approved the human subject research (ID 1502–0001; PRMC-22–037; STUDY-22–00928) from 9/23/2022 to 9/19/2023.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.Abstract 650 Figure 1Trial schema for neoadjuvant ezabenlimab or pembrolizumab with anti-SlRPα antibody

Despite no apparent defects in T cell priming and recruitment to tumors, a large subset of T cell rich tumors fail to respond to immune checkpoint blockade (ICB). We leveraged a neoadjuvant anti-PD-1 trial in patients with hepatocellular carcinoma (HCC), as well as additional samples collected from patients treated off-label, to explore correlates of response to ICB within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13 + CH25H + IL-21 + PD-1 + CD4 + T helper cells (“CXCL13 + T H ”) and Granzyme K + PD-1 + effector-like CD8 + T cells, whereas terminally exhausted CD39 hi TOX hi PD-1 hi CD8 + T cells dominated in nonresponders. CD4 + and CD8 + T cell clones that expanded post-treatment were found in pretreatment biopsies. Notably, PD-1 + TCF-1 + (Progenitor-exhausted) CD8 + T cells shared clones mainly with effector-like cells in responders or terminally exhausted cells in nonresponders, suggesting that local CD8 + T cell differentiation occurs upon ICB. We found that these Progenitor CD8 + T cells interact with CXCL13 + T H within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or “mregDC”. These results suggest that discrete intratumoral niches that include mregDC and CXCL13 + T H control the differentiation of tumor-specific Progenitor exhasuted CD8 + T cells following ICB. Response to anti-PD-1 in patients with hepatocellular carcinoma is associated with clonal expansion of intratumoral CXCL13 + CD4 + helper T cells and effector-like CD8 + T cells, and local dendritic cells enriched in expression of maturation and regulatory molecules help facilitate CD8 + T cell differentiation.

Natural killer (NK) cells are commonly reduced in human tumors, enabling many to evade surveillance. Here, we sought to identify cues that alter NK cell activity in tumors. We found that, in human lung cancer, the presence of NK cells inversely correlated with that of monocyte-derived macrophages (mo-macs). In a murine model of lung adenocarcinoma, we show that engulfment of tumor debris by mo-macs triggers a pro-tumorigenic program governed by triggering receptor expressed on myeloid cells 2 (TREM2). Genetic deletion of Trem2 rescued NK cell accumulation and enabled an NK cell-mediated regression of lung tumors. TREM2 + mo-macs reduced NK cell activity by modulating interleukin (IL)-18/IL-18BP decoy interactions and IL-15 production. Notably, TREM2 blockade synergized with an NK cell-activating agent to further inhibit tumor growth. Altogether, our findings identify a new axis, in which TREM2 + mo-macs suppress NK cell accumulation and cytolytic activity. Dual targeting of macrophages and NK cells represents a new strategy to boost antitumor immunity. In non-small cell lung cancer, the presence of monocyte-derived macrophages inversely correlates with the presence of NK cells. Merad and colleagues propose that when monocytes phagocytose tumor debris they express TREM2, become pro-tumorigenic, and suppress NK cell recruitment and activation in tumors.