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Mechanism of Response and Resistance to CAR T Cell Therapies


Gholamin, Sharareh (2023) Mechanism of Response and Resistance to CAR T Cell Therapies. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/jf79-pv58.


While CAR T cell therapy has demonstrated remarkable success in treating leukemia, lymphoma, and multiple myeloma, its effectiveness in treating solid tumors, such as glioblastoma (GBM), remains limited. It is imperative to comprehend the mechanisms that hinder the efficacy of CAR T cell therapies and to devise strategies to counteract tumor resistance. In this study, we hypothesized that disruptions in the cell-intrinsic interferon (IFN) signaling pathway contribute to the establishment of an immunosuppressive tumor microenvironment in solid tumors, ultimately rendering solid tumor cells resistant to CAR T cell-mediated elimination.

To investigate this, we established syngeneic models of IFN signaling-deficient tumors in the context of murine IL-13Ra2 targeted CAR T cell therapy. Our findings revealed that these models indeed manipulate the tumor microenvironment (TME), leading to a resistance to CAR T cell therapy. Notably, we observed variations in gene expression related to IFN signaling components and cytokines between IFN signaling-deficient tumor cells and wild type (WT) tumor cells following CAR T cell treatment.

Moreover, employing techniques such as single-cell RNA sequencing and mass cytometry analysis, we scrutinized the immune cell infiltrates within tumors lacking IFN signaling in comparison to WT controls. This in-depth analysis identified key immune-mediated factors contributing to the resistance observed in tumors with disrupted Janus Kinase1 (JAK1/KO) signaling upon CAR T cell therapy. Specifically, CAR T cell-treated IFN signaling-deficient tumors exhibited reduced T-cell transcripts, characterized by a decline in the frequency of CD8-early active and CD8-native like T cells. Conversely, an increase in regulatory and follicular T cells, exhausted endogenous T cells, and even exhausted CAR T cells was observed in treated IFN signaling-deficient tumors when contrasted with treated WT tumors. Furthermore, our analyses underscored the enrichment of genes associated with fibroblasts, neutrophils, and myeloid cells within IFN signaling-deficient tumors in contrast to WT tumors.

These findings collectively suggest that the immune suppressive communication within the IFN signaling-deficient tumor microenvironment could arise due to the differential enhancement of receptor-ligand interactions, such as SPP1+ tumor-associated macrophages (TAMs) and CD44+ cancer-associated fibroblasts (CAFs), along with interactions involving integrins on other cell lineages. To address the resistance observed in IFN-deficient tumors, we devised strategies aimed at enhancing the efficacy of CAR T cell therapy by promoting the recruitment of activated immune cells and reshaping the tumor microenvironment.

We next conducted an analysis of immune signatures in 32 GBM patients who exhibited progressive disease following CAR T cell treatment, comparing them with patients who displayed relatively stable disease or showed signs of improvement. Our investigations revealed the presence of fibroblasts and SPP1+ APOE+ C1QA+ C1QC+ myeloid cells within the GBM signatures, which are associated with immune suppression and resistance to therapy. Notably, patients with GBM who displayed a relatively stable treatment response and enhanced T cell recruitment demonstrated distinct expression patterns of interferon regulatory factors (IRFs) compared to patients with less favorable treatment responses.

These findings offer insights into the intricate interplay between tumor-intrinsic driver mutations, the composition of the tumor microenvironment, and the responsiveness of solid tumors to CAR T cell therapy. Importantly, our study provides potential avenues for addressing resistance in tumors that do not respond to interferon-based therapies.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Cancer immunotherapy, resistance to CAR T cells, glioblastoma
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Biology
Thesis Availability:Not set
Research Advisor(s):
  • Bronner, Marianne E. (advisor)
  • Brown, Christine (co-advisor)
  • Forman, Stephen (co-advisor)
Thesis Committee:
  • Shapiro, Mikhail G. (chair)
  • Baltimore, David L.
  • Bronner, Marianne E.
  • Heath, James R.
  • Brown, Christine
  • Ribas, Antoni
  • Forman, Stephen
Defense Date:9 June 2023
Funding AgencyGrant Number
Parker Institute for Cancer ImmunotherapyUNSPECIFIED
Brenn FoundationUNSPECIFIED
Record Number:CaltechTHESIS:06132023-010825748
Persistent URL:
Related URLs:
URLURL TypeDescription Engineered IL13 variants direct specificity of IL13Rα2-targeted CAR T cell therapy CAR T cell therapy reshapes the tumor microenvironment to promote host antitumor immune repsonses in glioblastoma IFNγ Is Critical for CAR T Cell-Mediated Myeloid Activation and Induction of Endogenous Immunity
Gholamin, Sharareh0000-0001-7425-6074
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:16115
Deposited By: Sharareh Gholamin
Deposited On:16 Jun 2023 16:01
Last Modified:14 Aug 2023 19:04

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