A Sampling of Highlights from the Literature

T cells engineered to express personalized neoantigen-specific TCRs cause tumor regression (from Wikimedia Commons).Different approaches to adoptive cell therapy are being evaluated in various clinical trials. Parkhurst and colleagues report results from a phase 2 clinical trial evaluating autologous peripheral blood lymphocytes (PBLs) genetically modified via retroviral transduction to express neoantigen-reactive T-cell receptors (TCRs) isolated from tumor-infiltrating lymphocytes from the patients. Among the seven patients with metastatic colorectal cancer who were treated, three had short-duration partial responses, as assessed by RECIST 1.1 criteria. The data provide support for further clinical evaluation of T cells genetically modified to express personalized neoantigen-reactive TCRs.Parkhurst M, …, Rosenberg SA. Nat Med 2024 July 11. DOI:10.1038/s41591-024-03109-0.Treg accumulation at peri-lymphatic regions in tumor stroma limits antitumor immunity (from Manu5 via Wikimedia Commons).What makes the tumor microenvironment (TME) immunosuppressive is yet to be completely characterized. To address this knowledge gap, You and colleagues used advanced multiplex imaging techniques to characterize the distribution of immune cells in the TME. In a colorectal cancer model, regulatory T cells (Treg) are recruited to peri-lymphatic regions in the tumor stroma by mature dendritic cells enriched in immunoregulatory molecules (mregDCs). Treg–mregDC crosstalk results in reduced transportation of tumor antigens into the draining lymph node, limiting initiation of antitumor T-cell responses. These findings highlight how spatial technologies can enhance understanding of the impact of TME immune architecture on antitumor immunity.You S, …, Mao K. Cancer Cell 2024 July 18;42:1415–1433.e12.Profiling reveals NK-cell heterogeneity across tumor types (from NIAID/NIH via Flickr).Two studies provide a new understanding of the heterogeneity of human natural killer (NK) cells in healthy tissues and the tumor microenvironment. Netskar and colleagues generated a single-cell transcriptional reference map of healthy human blood- and tissue-derived NK cells and used it to analyze the transcriptomes of NK cells from seven types of solid tumors, identifying six functionally distinct cellular states of NK cells. Rebuffet and colleagues also used single-cell analyses, identifying three main NK-cell subsets in healthy human blood and finding a lack of correlation between circulating and tumor-infiltrating NK cells across 22 tumor types. These two studies provide resources to facilitate the development of effective NK cell–based cancer immunotherapies.Netskar H, …, Malmberg KJ. Nat Immunol 2024 July 2;25,1445–1459.Rebuffet L, …, Vivier E. Nat Immunol 2024 July 2;25,1474–1488.Tr1 cells can inhibit antitumor immune responses (from NIH via picryl).How to design cancer vaccines to activate helper, rather than immunosuppressive, CD4+ T cells is unclear. Using mouse sarcoma models, Sultan and colleagues demonstrate that vaccines with low doses of MHC-II–restricted peptides induce tumor rejection, whereas vaccines with high doses of the same neoantigen (HDVax) inhibit rejection by inducing type 1 regulatory T (Tr1) cells. Tr1 cells suppress tumor rejection by selectively killing type 1 conventional dendritic cells (cDC1). Tr1-mediated suppression of tumor rejection can be overcome in several ways, including the blockade of LILRB4, a marker of Tr1 cells. The data provide new insight into cellular mechanisms inhibiting immune control of cancer.Sultan H, …, Schreiber RD. Nature 2024 July 24;632,182–191.Researchers uncover how IL33 is released from CSCs to promote SCC progression (from jmol via Wikimedia Commons).Understanding the context of the pro- and antitumorigenic effects of IL33 is important if it is to be targeted therapeutically. In squamous cell carcinoma (SCC), Erickson and colleagues, find that activation of NRF2 in cancer stem cells (CSCs) causes nuclear-to-cytoplasmic translocation of IL33. Once in the cytoplasm, ATG9B mediates the formation of IL33-containing AXNA1+ large oncosomes, which are released from CSCs and target myeloid precursors expressing the receptor for AXNA1, FPR2, thus inducing their differentiation to an immunosuppressive phenotype. Eliminating ATG9B activity reduces tumor size and invasiveness, suggesting this pathway is a target to reduce the protumorigenic effects of IL33.Erickson HL, …, Oshimori N. Immunity 2024 July 29;57:1908–1922.e6.TLS formation can be driven by endothelial cell–T cell cross-talk (from Fig. 1 of Weng and colleagues Sci Rep 2024).Research into the biology of autoimmunity can provide new insights into tumor immunology, as highlighted by Zhou and colleagues who show that although cGAS–STING hyperactivation leads to lung inflammation that is associated with the formation of tertiary lymphoid structures (TLS), the same pathway promotes antitumor immunity in the Lewis lung carcinoma model. TLS establishment is facilitated by cGAS activation in endothelial cells, which leads to CCL5 production, and cGAS activation in CD8+ T cells, which increases expression of the CCL5 receptor CCR5. Consistent with the antitumorigenic role of this pathway, data from patients with cancer show an association between CCL5 levels and survival.Zhou R, …, Gao D. Sci Immunol 2024 Aug 2;9,eadk2612.