Immunotherapy targeting different immune compartments in combination with radiation therapy induces regression of resistant tumors

Nils-Petter Rudqvist, Maud Charpentier, Claire Lhuillier, Erik Wennerberg, Sheila Spada, Caroline Sheridan, Xi Kathy Zhou, Tuo Zhang, Silvia C. Formenti, Jennifer S. Sims, Alicia Alonso and Sandra Demaria ()
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Nils-Petter Rudqvist: Weill Cornell Medicine
Maud Charpentier: Weill Cornell Medicine
Claire Lhuillier: Weill Cornell Medicine
Erik Wennerberg: Weill Cornell Medicine
Sheila Spada: Weill Cornell Medicine
Caroline Sheridan: Weill Cornell Medicine
Xi Kathy Zhou: Weill Cornell Medicine
Tuo Zhang: Weill Cornell Medicine
Silvia C. Formenti: Weill Cornell Medicine
Jennifer S. Sims: Memorial Sloan Kettering Cancer Center
Alicia Alonso: Weill Cornell Medicine
Sandra Demaria: Weill Cornell Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-23

Abstract: Abstract Radiation therapy (RT) increases tumor response to CTLA-4 inhibition (CTLA4i) in mice and in some patients, yet deep responses are rare. To identify rational combinations of immunotherapy to improve responses we use models of triple negative breast cancer highly resistant to immunotherapy in female mice. We find that CTLA4i promotes the expansion of CD4+ T helper cells, whereas RT enhances T cell clonality and enriches for CD8+ T cells with an exhausted phenotype. Combination therapy decreases regulatory CD4+ T cells and increases effector memory, early activation and precursor exhausted CD8+ T cells. A combined gene signature comprising these three CD8+ T cell clusters is associated with survival in patients. Here we show that targeting additional immune checkpoints expressed by intratumoral T cells, including PD1, is not effective, whereas CD40 agonist therapy recruits resistant tumors into responding to the combination of RT and CTLA4i, indicating the need to target different immune compartments.

Date: 2023
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DOI: 10.1038/s41467-023-40844-3

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