Both intratumoral regulatory T cell depletion and CTLA-4 antagonism are required for maximum efficacy of anti-CTLA-4 antibodies
Name
lax-et-al-2023-both-intratumoral-regulatory-t-cell-depletion-and-ctla-4-antagonism-are-required-for-maximum-efficacy-of.pdf
Description
Published version
Size
1.19 MB
Format
Adobe PDF
Checksum (MD5)
426c91d34f3caec4e69cdfeeeb482109
Author(s)
Lax, Brianna M
Palmeri, Joseph R
Lutz, Emi A
Sheen, Allison
Stinson, Jordan A
Duhamel, Lauren
Santollani, Luciano
Kennedy, Alan
Rothschilds, Adrienne M
Spranger, Stefani
Date Issued
July 24, 2023
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Citation
B.M. Lax,J.R. Palmeri,E.A. Lutz,A. Sheen,J.A. Stinson,L. Duhamel,L. Santollani,A. Kennedy,A.M. Rothschilds,S. Spranger,D.M. Sansom, & K.D. Wittrup, Both intratumoral regulatory T cell depletion and CTLA-4 antagonism are required for maximum efficacy of anti-CTLA-4 antibodies, Proc. Natl. Acad. Sci. U.S.A. 120 (31) e2300895120.
Version
Final published version
Abstract
Anti-CTLA-4 antibodies have successfully elicited durable tumor regression in the clinic; however, long-term benefit is limited to a subset of patients for select cancer indications. The incomplete understanding of their mechanism of action has hindered efforts at improvement, with conflicting hypotheses proposing either antagonism of the CTLA-4:B7 axis or Fc effector-mediated regulatory T cell (Treg) depletion governing efficacy. Here, we report the engineering of a nonantagonistic CTLA-4 binding domain (b1s1e2) that depletes intratumoral Tregs as an Fc fusion. Comparison of b1s1e2-Fc to 9d9, an antagonistic anti-CTLA-4 antibody, allowed for interrogation of the separate contributions of CTLA-4 antagonism and Treg depletion to efficacy. Despite equivalent levels of intratumoral Treg depletion, 9d9 achieved more long-term cures than b1s1e2-Fc in MC38 tumors, demonstrating that CTLA-4 antagonism provided additional survival benefit. Consistent with prior reports that CTLA-4 antagonism enhances priming, treatment with 9d9, but not b1s1e2-Fc, increased the percentage of activated T cells in the tumor-draining lymph node (tdLN). Treg depletion with either construct was restricted to the tumor due to insufficient surface CTLA-4 expression on Tregs in other compartments. Through intratumoral administration of diphtheria toxin in Foxp3-DTR mice, we show that depletion of both intratumoral and nodal Tregs provided even greater survival benefit than 9d9, consistent with Treg-driven restraint of priming in the tdLN. Our data demonstrate that anti-CTLA-4 therapies require both CTLA-4 antagonism and intratumoral Treg depletion for maximum efficacy—but that potential future therapies also capable of depleting nodal Tregs could show efficacy in the absence of CTLA-4 antagonism.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution-NonCommercial-NoDerivatives
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DOI of Published Version
10.1073/pnas.2300895120
