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Supplementary Figure S5 from Efficacy of CAR T-cell Therapy in Large Tumors Relies upon Stromal Targeting by IFNγ

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posted on 2023-03-30, 22:42 authored by Ana Textor, Joanna J. Listopad, Lara Le Wührmann, Cynthia Perez, Anna Kruschinski, Markus Chmielewski, Hinrich Abken, Thomas Blankenstein, Jehad Charo

Non-hematopoietic cells compose the majority of the SKOV3 tumor stroma

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ARTICLE ABSTRACT

Adoptive T-cell therapy using chimeric antigen receptor–modified T cells (CAR-T therapy) has shown dramatic efficacy in patients with circulating lymphoma. However, eradication of solid tumors with CAR-T therapy has not been reported yet to be efficacious. In solid tumors, stroma destruction, due to MHC-restricted cross-presentation of tumor antigens to T cells, may be essential. However, CAR-Ts recognize antigens in an MHC-independent manner on cancer cells but not stroma cells. In this report, we show how CAR-Ts can be engineered to eradicate large established tumors with provision of a suitable CD28 costimulatory signal. In an HER2–dependent tumor model, tumor rejection by HER2–specific CAR-Ts was associated with sustained influx and proliferation of the adoptively transferred T cells. Interestingly, tumor rejection did not involve natural killer cells but was associated instead with a marked increase in the level of M1 macrophages and a requirement for IFNγ receptor expression on tumor stroma cells. Our results argue that CAR-T therapy is capable of eradicating solid tumors through a combination of antigen-independent stroma destruction and antigen-specific tumor cell targeting. Cancer Res; 74(23); 6796–805. ©2014 AACR.

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