One CD4+TCR and One CD8+TCR Targeting Autochthonous Neoantigens Are Essential and Sufficient for Tumor Eradication

Author:

Wolf Steven P.12ORCID,Anastasopoulou Vasiliki34ORCID,Drousch Kimberley3ORCID,Diehl Markus I.1ORCID,Engels Boris1ORCID,Yew Poh Yin5ORCID,Kiyotani Kazuma6ORCID,Nakamura Yusuke6ORCID,Schreiber Karin12ORCID,Schreiber Hans127ORCID,Leisegang Matthias234ORCID

Affiliation:

1. 1Department of Pathology, The University of Chicago, Chicago, Illinois.

2. 2David and Etta Jonas Center for Cellular Therapy, The University of Chicago, Chicago, Illinois.

3. 3Institute of Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

4. 4German Cancer Consortium (DKTK), partner site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany.

5. 5Department of Medicine, The University of Chicago, Chicago, Illinois.

6. 6Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan.

7. 7Committee on Cancer Biology, Committee on Immunology and the Cancer Center, The University of Chicago, Chicago, Illinois.

Abstract

Abstract Purpose: To achieve eradication of solid tumors, we examined how many neoantigens need to be targeted with how many T-cell receptors (TCR) by which type of T cells. Experimental Design: Unmanipulated, naturally expressed (autochthonous) neoantigens were targeted with adoptively transferred TCR-engineered autologous T cells (TCR-therapy). TCR-therapy used CD8+ T-cell subsets engineered with TCRs isolated from CD8+ T cells (CD8+TCR-therapy), CD4+ T-cell subsets engineered with TCRs isolated from CD4+ T cells (CD4+TCR-therapy), or combinations of both. The targeted tumors were established for at least 3 weeks and derived from primary autochthonous cancer cell cultures, resembling natural solid tumors and their heterogeneity as found in humans. Results: Relapse was common with CD8+TCR-therapy even when targeting multiple different autochthonous neoantigens on heterogeneous solid tumors. CD8+TCR-therapy was only effective against homogenous tumors artificially derived from a cancer cell clone. In contrast, a combination of CD8+TCR-therapy with CD4+TCR-therapy, each targeting one neoantigen, eradicated large and established solid tumors of natural heterogeneity. CD4+TCR-therapy targeted a mutant neoantigen on tumor stroma while direct cancer cell recognition by CD8+TCR-therapy was essential for cure. In vitro data were consistent with elimination of cancer cells requiring a four-cell cluster composed of TCR-engineered CD4+ and CD8+ T cells together with antigen-presenting cells and cancer cells. Conclusions: Two cancer-specific TCRs can be essential and sufficient to eradicate heterogeneous solid tumors expressing unmanipulated, autochthonous targets. We demonstrate that simplifications to adoptive TCR-therapy are possible without compromising efficacy.

Funder

National Institutes of Health

Deutsche Forschungsgemeinschaft

Einstein Stiftung Berlin

Berliner Krebsgesellschaft e.V

Publisher

American Association for Cancer Research (AACR)

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