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Intratumoral heterogeneity in cancer progression and response to immunotherapy

Abstract

Most (if not all) tumors emerge and progress under a strong evolutionary pressure imposed by trophic, metabolic, immunological, and therapeutic factors. The relative impact of these factors on tumor evolution changes over space and time, ultimately favoring the establishment of a neoplastic microenvironment that exhibits considerable genetic, phenotypic, and behavioral heterogeneity in all its components. Here, we discuss the main sources of intratumoral heterogeneity and its impact on the natural history of the disease, including sensitivity to treatment, as we delineate potential strategies to target such a detrimental feature of aggressive malignancies.

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Fig. 1: Principles governing ITH.
Fig. 2: Spatial and temporal intratumoral heterogeneity in malignant cells.
Fig. 3: Intratumoral heterogeneity in the lymphoid compartment.

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Acknowledgements

We thank G. Inghirami (Weill Cornell Medical College, New York, NY, US) for kindly providing micrographs included in Fig. 2, as well as K. Gouin and S. Knott (Cedars Sinai, Los Angeles, CA, US) for kindly providing UMAPs included in Fig. 3. I.V. is supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC, IG 2017 #20417) and a startup grant from the Italian Institute for Genomic Medicine (Candiolo, Turin, Italy) and Compagnia di San Paolo (Torino, Italy). E.S. is an incumbent of the Lisa and Jeffrey Aronin Family Career Development Chair, and she is supported by grants from the European Research Council (#ERC801655), The Israeli Science Foundation (#1881/19), and Minerva. S.L. is supported by the National Breast Cancer Foundation of Australia and the Breast Cancer Research Foundation. L.G. is supported by a Breakthrough Level 2 grant from the US Department of Defense (DoD), Breast Cancer Research Program (BRCP) (#BC180476P1), by the 2019 Laura Ziskin Prize in Translational Research (#ZP-6177, PI: Formenti) from the Stand Up to Cancer (SU2C) program, by a Mantle Cell Lymphoma Research Initiative (MCL-RI, PI: Chen-Kiang) grant from the Leukemia and Lymphoma Society (LLS), by a startup grant from the department of radiation oncology at Weill Cornell Medicine (New York, US), by a Rapid Response Grant from the Functional Genomics Initiative (New York, US), by industrial collaborations with Lytix (Oslo, Norway) and Phosplatin (New York, US), and by donations from Phosplatin (New York, US), the Luke Heller TECPR2 Foundation (Boston, US), and Sotio (Prague, Czech Republic).

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I.V. and L.G. conceived the review and wrote the first version of the manuscript with constructive input from E.S. and S.L. I.V. prepared display items under the supervision of L.G. All authors approve the final version of the article and figures.

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Correspondence to Ilio Vitale or Lorenzo Galluzzi.

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Competing interests

S.L. receives research funding to her institution from Novartis, Bristol Meyers Squibb, Merck, Roche-Genentech, Puma Biotechnology, Pfizer, Eli Lilly, and Seattle Genetics, and she has acted as a noncompensated consultant for Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca, and Roche-Genentech, as well as compensated consultant for Aduro Biotech, Novartis, GlaxoSmithKline, and G1 Therapeutics. L.G. has received research funding from Lytix and Phosplatin, as well as consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, The Longevity Labs, Inzen, and the Luke Heller TECPR2 Foundation.

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Peer review information Hannah Stower was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Vitale, I., Shema, E., Loi, S. et al. Intratumoral heterogeneity in cancer progression and response to immunotherapy. Nat Med 27, 212–224 (2021). https://doi.org/10.1038/s41591-021-01233-9

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