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Acute myeloid leukemia (AML) has not benefited from innovative immunotherapies, mainly because of the lack of actionable immune targets. Using an original proteogenomic approach, we analyzed the major histocompatibility complex class I (MHC class I)-associated immunopeptidome of 19 primary AML samples and identified 58 tumor-specific antigens (TSAs). These TSAs bore no mutations and derived mainly (86%) from supposedly non-coding genomic regions. Two AML-specific aberrations were instrumental in the biogenesis of TSAs, intron retention, and epigenetic changes. Indeed, 48% of TSAs resulted from intron retention and translation, and their RNA expression correlated with mutations of epigenetic modifiers (e.g., DNMT3A). AML TSA-coding transcripts were highly shared among patients and were expressed in both blasts and leukemic stem cells. In AML patients, the predicted number of TSAs correlated with spontaneous expansion of cognate T cell receptor clonotypes, accumulation of activated cytotoxic T cells, immunoediting, and improved survival. These TSAs represent attractive targets for AML immunotherapy. [Display omitted] • The proteogenomic features of 58 acute myeloid leukemia (AML)-specific antigens • AML antigens result mainly from epigenetic changes and intron retention • AML antigens are coded by transcripts expressed in leukemic blasts and stem cells • AML antigens elicit CD8 T cell responses in vitro and in vivo The lack of suitable targets is the main obstacle to immunotherapy of acute myeloid leukemia (AML). Ehx et al. reveal the structure and genomic origin of 58 AML-specific antigens. Epigenetic changes and intron retention are instrumental in the biogenesis of these antigens that represent attractive targets for AML immunotherapy. [ABSTRACT FROM AUTHOR]

Our understanding of tumor-infiltrating lymphocytes (TILs) is rapidly expanding beyond T cell-centric perspectives to include B cells and plasma cells, collectively referred to as TIL-Bs. In many cancers, TIL-Bs carry strong prognostic significance and are emerging as key predictors of response to immune checkpoint inhibitors. TIL-Bs can perform multiple functions, including antigen presentation and antibody production, which allow them to focus immune responses on cognate antigen to support both T cell responses and innate mechanisms involving complement, macrophages, and natural killer cells. In the stroma of the most immunologically "hot" tumors, TIL-Bs are prominent components of tertiary lymphoid structures, which resemble lymph nodes structurally and functionally. Additionally, TIL-Bs participate in a variety of other lympho-myeloid aggregates and engage in dynamic interactions with the tumor stroma. Here, we summarize our current understanding of TIL-Bs in human cancer, highlighting the compelling therapeutic opportunities offered by their unique tumor recognition and effector mechanisms., Competing Interests: Declaration of interests The authors declare no competing interests., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Tumor-infiltrating B cells and plasma cells have emerged as critical players in anti-tumor immunity. A recent report in Nature shows that IgA antibodies produced by these cells can enter tumor cells by transcytosis, impede oncogenic signals, and facilitate T cell-mediated cytotoxicity. These findings reveal a promising new mechanism to exploit for immunotherapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)