Isoform specific anti-TGFβ therapy enhances antitumor efficacy in mouse models of cancer

Aditi Gupta, Sadna Budhu, Kelly Fitzgerald, Rachel Giese, Adam O. Michel, Aliya Holland, Luis Felipe Campesato, Jacques van Snick, Catherine Uyttenhove, Gerd Ritter, Jedd D. Wolchok, Taha Merghoub

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

TGFβ is a potential target in cancer treatment due to its dual role in tumorigenesis and homeostasis. However, the expression of TGFβ and its inhibition within the tumor microenvironment has mainly been investigated in stroma-heavy tumors. Using B16 mouse melanoma and CT26 colon carcinoma as models of stroma-poor tumors, we demonstrate that myeloid/dendritic cells are the main sources of TGFβ1 and TGFβ3. Depending on local expression of TGFβ isoforms, isoform specific inhibition of either TGFβ1 or TGFβ3 may be effective. The TGFβ signature of CT26 colon carcinoma is defined by TGFβ1 and TGFβ1 inhibition results in tumor delay; B16 melanoma has equal expression of both isoforms and inhibition of either TGFβ1 or TGFβ3 controls tumor growth. Using T cell functional assays, we show that the mechanism of tumor delay is through and dependent on enhanced CD8+ T cell function. To overcome the local immunosuppressive environment, we found that combining TGFβ inhibition with immune checkpoint blockade results in improved tumor control. Our data suggest that TGFβ inhibition in stroma poor tumors shifts the local immune environment to favor tumor suppression.

Original languageEnglish (US)
Article number1296
JournalCommunications Biology
Volume4
Issue number1
DOIs
StatePublished - Dec 2021
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences
  • Medicine (miscellaneous)

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