A Sampling of Highlights from the Literature

STK11 and KEAP1 mutations are associated with NSCLC resistance to anti–PD-1/PD-L1 (from NCI\Huntsman Cancer Institute at the Univ. of Utah via NCI Visuals)Determining whether non–small cell lung cancer (NSCLC) patients will benefit from adding anti-CTLA4 therapy to anti–PD-1/PD-L1 is challenging. By analyzing data from a phase III trial of NSCLC patients treated with chemotherapy, chemotherapy and the anti–PD-L1 durvalumab, or chemotherapy, durvalumab, and the anti-CTLA4 tremelimumab, Skoulidis and colleagues show that patients whose tumors have STK11 and/or KEAP1 mutations benefit from chemotherapy, durvalumab, and tremelimumab, but not from chemotherapy and durvalumab. In mouse models, dual anti-CTLA4 and anti–PD-1 overcomes STK11 and KEAP1 mutation–associated immune suppressive features in the tumor microenvironment, retaining CD4+ effector cells and reprogramming myeloid cells to a tumoricidal phenotype.Skoulidis F, …, Heymach JV.Nature2024 Oct 9;635,462–471.Engineered Escherichia coli Nissle 1917 serve as neoantigen vaccines (from NIAID via NIH Flickr)Bacteria have potential as vectors for delivering therapeutic payloads to tumors. Through multiple engineering steps, Redenti and colleagues generate Escherichia coli Nissle 1917 expressing arrays of neoantigens that are effectively delivered to antigen-presenting cells for both MHC class I and MHC class II presentation. These bacteria are effective tumor neoantigen vaccines in models of primary and metastatic colorectal cancer and melanoma, showing efficacy when administered either intratumorally or intravenously through the induction of neoantigen-specific CD4+ and CD8+ T cells. The data highlight the potential of bacterial engineering for cancer vaccine development.Redenti A, …, Arpaia N.Nature2024 Oct 16;635,453–461.Trafficking of T cells to the brain during immune checkpoint inhibitor therapy (from Jesus Leonardo Rondon Tapia via Wikimedia Commons)Immune checkpoint therapy improves outcomes for patients with melanoma that metastasizes to the brain, but how T cells traffic to the brain is incompletely understood. Using intravital two-photon microscopy in intracranial mouse models of melanoma, Messmer and colleagues demonstrate that expression of the endothelial adhesion molecule ICAM-1 on peritumoral venous vessels (PVVs) facilitates recruitment of T cells into the brain following anti-CTLA4 and anti–PD-1 therapy. The translational potential of the data is highlighted by the observation that ICAM-1 expression by PVV-like vessels correlated with intratumoral T-cell infiltration in human brain metastases.Messmer J, ..., Winkler.Immunity2024 Nov 12;57,2688-2703.e11.Amyloid precursor protein on T cells could be an immune checkpoint target for cancer (Via RawPixel)Identifying new immune checkpoints could improve cancer immunotherapy. Jeon and colleagues report contactin-4 (CNTN4) as a new target for immune checkpoint therapy. They find CNTN4, a synaptic cell adhesion molecule expressed on multiple human cancers and murine tumor models, binds with amyloid precursor protein, a neurine outgrowth and adhesion protein expressed on T cells, inhibiting T-cell activation. Antibody blockade of the interaction in mice inhibits tumor growth as well as lymphocyte infiltration into tumors. The clinical relevance of this is highlighted by the observation that CNTN4 expression is associated with poor outcomes and lowered T-cell cytotoxic activity in patients with cancer.Jeon B, ..., Park H.Science Immunology2024 Oct 11;9,eadk7237.G protein–coupled receptors could be targets for cancer immunotherapy (from Fred the Oyster via Wikimedia Commons)Two studies identify members of the diverse family of G protein–coupled receptors—GPR34 and GPR65—as potential targets for cancer immunotherapy. Yan and colleagues find that the lysophosphatidylserine (LysoPS) receptor GPR34 is highly expressed on type 1 innate lymphoid cells (ILC1s), and that LysoPS accumulates in the tumor microenvironment and inhibits ILC1-mediated antitumor immunity via GPR34. Bagchi and colleagues show that tumor-associated macrophages expressing the acid-sensing receptor GPR65 detect the accumulation and breakdown of oleic acid, driving tumor growth in models of obesity-associated colorectal cancer and hepatocellular carcinoma. In both studies, genetic and/or pharmacologic targeting of the relevant G protein–coupled receptor reduces tumor growth, highlighting their potential as immunotherapeutic targets.Yan J, …, Zhou R.Nat Immunol2024 Oct 2;25,2057–2067.Bagchi S, …, Engelman EG.Sci Immunol2024 Oct 18;9,eadg6453.RNA-seq atlas of B cells and plasma cells in cancer in the new interactive Shiny tool (from Nephron via Wikimedia Commons)How B cells shape the tumor microenvironment has yet not been comprehensively characterized. Through single-cell RNA sequencing (scRNA-seq) of intratumoral B cells and plasma cells from multiple cancers, Fitzsimons and colleagues generate an scRNA-seq atlas of B cells in cancer. Using the data, the authors identify B-cell clusters that are associated with response to checkpoint inhibitor therapy, including a positive correlation between naive B cells and response. Further analysis of interactions between B and T cells highlights a role for CXCL13/CXCR5 interactions in influencing response to checkpoint inhibitor therapy. The data can be explored through the freely available interactive Shiny tool.Fitzsimons E, ..., Litchfield K.Cancer Cell2024 Oct 14;42,1784–1797.e4.