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Incomplete surgical removal of a solid tumor increases a patient's risk for local tumor recurrence. Using xenograft models of incomplete excision of pancreatic ductal adenocarcinoma (PDAC) and triple-negative breast cancer (TNBC), Uslu and colleagues show that intra-operative application of mesothelin-targeted chimeric antigen receptor (CAR) T cells in a fibrin glue–based carrier results in clearance of residual tumor cells and increased survival compared with the same application of the CAR T cells into the tumor cavity in the absence of fibrin gel. The treatment had limited on-target off-tumor toxicity and did not lead to wound healing complications, supporting its clinical evaluation.

Uslu U, …, June CH. Sci Adv 2023 January 11;9:eade2526.

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Neutrophils have a complex role in cancer. They often promote tumor growth and metastasis but can exert antitumor activity in certain contexts. Using a combination of TNF, anti-CD40, and tumor-binding antibody, Linde and colleagues show in multiple preclinical models of cancer that neutrophils can be harnessed therapeutically, causing tumor regression and reducing metastatic seeding. The combination leads to neutrophil activation via complement component C5A receptor 1, inducing leukotriene B4 secretion, xanthine oxidase–mediated reactive oxygen species production, oxidative damage, and T cell–independent tumor clearance. The same combination activates human neutrophils in vitro, suggesting its potential for clinical translation.

Linde IL, …, Engleman EG. Cancer Cell 2023 January 26. DOI:10.1016/j.ccell.2023.01.002.

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How PD-1 expression on regulatory T cells (Treg) impacts T-cell function is equivocal. Kim and colleagues demonstrate that deletion or blocking of PD-1 on Tregs impairs their proliferation and suppressive function, thereby delaying tumor progression. Immune checkpoint blockade (ICB) reduced Treg number and altered Treg metabolism to favor lipid metabolism. The data provide new insight into ways in which ICB alters the tumor microenvironment to favor antitumor responses.

Kim MJ, …, Ha SJ. Nat Immunol 2022 December 28;24:148–61.

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Resistance to CD8+ T cell–mediated killing through genomic inactivation of β2-microglobulin causes tumors to lose responsiveness to immune checkpoint blockade (ICB). De Vries and colleagues find that in DNA mismatch repair–deficient (MMR-d) colon cancer, responsiveness to ICB can be maintained in tumors with B2M inactivation through the activity of γδ T cells, predominantly Vδ1 and Vδ3 γδ T cells. These cells express PD1 and markers of cytotoxicity and kill HLA class I–deficient colon cancer cell lines and organoids, highlighting this immune subset's role in the efficacy of ICB in HLA I–negative, MMR-d colon cancer.

de Vries NL, …, Voest EE. Nature 2023 January 11;613:743–50.

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The mechanisms behind resistance to immunotherapy are not yet fully understood. In brain tumors, Kilian and colleagues show that MHC class II–mediated antigen presentation by infiltrating blood-borne myeloid cells contributes to antitumor responses that control tumor growth. Myeloid-cell loss of MHC class II leads to CD8+ T-cell dysfunction due to osteopontin-induced expression of TOX in CD8+ T cells, a process normally restricted by CD4+ T cell–mediated suppression of myeloid-cell expression of osteopontin. The data highlight that myeloid cells can have a role in modulating CD8+ T-cell function.

Kilian M, …, Platten M. Cancer Cell 2023 January 12. DOI:10.1016/j.ccell.2022.12.007.

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Not all patients respond to anti–PD-1/PD-L1 therapy. Thus, better understanding of the CD8+ T cells crucial for responsiveness to such therapy is needed. Wang and colleagues show in multiple patient datasets that an increase in intratumoral CD200+ T cells upon anti–PD-1 treatment correlates with improved clinical outcomes. Depletion of CD200+ T cells in multiple preclinical models of cancer reduces the efficacy of anti–PD-L1, and in vitro and in vivo analyses show CD200+CD8+ T cells have increased proliferative, cytokine secretion, and tumor-cell killing capacities compared with CD200CD8+ T cells. Together, the data suggest tumor infiltration by CD200+CD8+ T cells may be a predictor of response to anti–PD-1/PD-L1 therapy.

Wang X, …, Zhu B. Sci Trans Med 2023 January 18;15:eabn5029.