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Emerging evidence indicates that tumor-associated MHC-I–presented peptides can be generated from noncanonical transcripts. Two studies expand the landscape of such transcripts to include transcripts generated by mRNA splicing events between exons and transposable elements (TE). In patients with non–small cell lung cancer, Merlotti et al. identify CD8+ T cells that recognize tumor-specific HLA-I–bound peptides encoded by transcripts generated from exon–TE splicing junctions. Burbage et al. find that immunization with peptides derived from exon–TE splicing junctions slows tumor growth in several mouse tumor models. Together, the data suggest these peptides could be harnessed to develop therapeutic cancer vaccines or TCR-based cell therapies.

Merlotti A, …, Amigorena S. Sci Immunol 2023 February 3;8:eabm6359.

Burbage M, …, Amigorena S. Sci Immunol 2023 February 3;8:eabm6360.

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Use of chimeric-antigen receptors (CAR) to boost antitumor immune responses has shown success against hematological cancers, but efficacy in solid tumors is limited. Chockley et al. demonstrate that enhancing immune synapse formation by CAR natural killer cells, via addition of an intracellular scaffold binding site to the CAR construct, improves therapeutic efficacy in xenograft models. Mechanistically, the addition of the scaffold protein allows crosslinking that increases synaptic strength, polyfunctional cytokine production, and target killing, leading to extended survival in solid tumor models. The data show how fine-tuning CARs can improve efficacy in solid tumors.

Chockley PJ, …, Gottschalk S. Nat Biotechnol 2023 February 2. DOI:10.1038/s41587-022-01650-2

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Accumulation of tumor-infiltrating CD8+ tissue-resident memory T (TRM) cells is associated with improved response to immune checkpoint inhibitors (ICI) in melanoma, a “hot” tumor,” but their role in “colder” tumors like breast cancer is less clear. In mouse models of triple-negative breast cancer (TNBC), Virassamy et al. find a subset of CD69+CD103+CD8+ cells that phenotypically and transcriptionally resemble the TRM cells found in human TNBC. Combination ICI therapy expands this population of TRM-like cells, enhances their cytotoxic activity, and provides protection against tumor rechallenge. The data have clinical relevance as a gene signature from the TRM-like cells is associated with benefit in TNBC patients treated with ICIs.

Virassamy B, …, Loi S. Cancer Cell 2023 February 23;41,585–601.E8.

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Neutrophils are important modulators of adaptive immune responses, but how their function is shaped in the context of cancer is not fully understood. Gong et al. demonstrate in a model of metastatic breast cancer that neutrophils in lungs are suppressive compared to their counterparts in the bone marrow and blood. Mechanistically, lung-associated neutrophils have baseline immune-suppressive capacity that is amplified by tumor-associated factors. This process is facilitated by CD140+ mesenchymal cells in the lung stroma and their production of prostaglandin E2 (PGE2). The data suggest that targeting tissue-specific stromal factors could boost antitumor responses against metastases, as well as improve responses to immunotherapy.

Gong Z, …, Ren G. Sci Immunol 2023 February 17;8:eadd5204.

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CD40 signaling promotes antitumor immune responses, but the mechanisms behind this are not fully elucidated. In a study by Liu et al, the metabolic impact of CD40 signaling in macrophages is revealed. Activation of CD40 induces fatty acid oxidation and glutamine metabolism, which in turn facilitates epigenetic reprogramming that confers on macrophages an antitumor phenotype. The effects of agonistic CD40-based treatment are dependent on these metabolic changes, highlighting the potential to precondition macrophages prior to agonistic anti-CD40 therapy.

Liu P-S, …, Ho P-C. Nat Immunol 2023 February 23;24:452–462.

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Different tumor-draining lymph nodes have unique environments that can impact the efficacy of antitumor immune responses. By analyzing CD8+ T cells in the mediastinal lymph nodes (mLN) and inguinal LNs (iLN) draining KP tumors growing either in the lung or the flank, Zagorulya et al. find that type 1 conventional dendritic cells (cDC1) in the mLN, but not iLN, fail to induce effective CD8+ T-cell antitumor responses. The mLN is found to be an IFNγ-rich environment that promotes regulatory T–cell differentiation to a Th1-like phenotype, generating cells that suppress cDC1 priming of CD8+ T-cell antitumor responses. The data provide new insight into LN-specific factors affecting antitumor immune responses.

Zagorulya M, …, Spranger S. Immunity 2023 February 2;56:386–405.E10.