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Expression of the switch receptor PD1/IL15Rβ in MSLN-CAR-T cells overcomes PD1/PDL1 signaling in solid tumors

Zahra Shahosseini1,2, Tahereh Soltantoyeh3, Hamid Reza Mirzaei3

  • 1Department of Medical Biotechnology, School of Allied Medical Sciences, Iran University of Medical Sciences (IUMS), Hemmat Highway, Tehran, Iran.

Scientific Reports
|July 15, 2026
PubMed

Insights

Engineered CAR T cells overcome tumor immunosuppression by converting inhibitory signals into T cell activation. This enhances CAR T cell persistence and antitumor activity in solid tumors.

Area of Science:

  • Immunology
  • Oncology
  • Biotechnology

Background:

  • The tumor microenvironment (TME) suppresses chimeric antigen receptor (CAR) T cell efficacy in solid tumors via inhibitory receptors like PD1 and TIM3.
  • T memory stem cells (TSCMs) are crucial for CAR T cell persistence, and IL15 signaling promotes T cell memory.
  • Mesothelin (MSLN) is a target antigen for CAR T cell therapy in various solid tumors.

Purpose of the Study:

  • To engineer MSLN-CAR-T cells with a novel PD1/IL15Rβ switch receptor to overcome TME-mediated immunosuppression.
  • To enhance CAR T cell function, persistence, and antitumor activity against mesothelin-expressing solid tumors.

Main Methods:

  • Development of MSLN-CAR-T cells incorporating a PD1/IL15Rβ switch receptor.
  • Evaluation of antitumor activity against pancreatic and cervical cancer cell lines.
  • Assessment of T cell proliferation, cytokine production (IL-2, IFN-γ), exhaustion markers (PD1, TIM3), and memory phenotypes (CD45RO+/CCR7+) via flow cytometry, ELISA, and western blotting.

Main Results:

  • MSLN-PD1/IL15Rβ-CAR-T cells showed enhanced STAT5 phosphorylation, increased proliferation, and elevated IL-2/IFN-γ secretion compared to standard MSLN-CAR-T cells.
  • Engineered CAR T cells exhibited reduced PD1/TIM3 expression and an increased proportion of memory T cells (CD45RO+/CCR7+).
  • The switch receptor effectively converted PD1/PDL1 inhibitory signals into IL15-mediated STAT5 activation, overcoming immunosuppression.

Conclusions:

  • The PD1/IL15Rβ switch receptor successfully overcomes PDL1-mediated immunosuppression in MSLN-CAR-T cells.
  • This engineered CAR T cell strategy improves T cell function, proliferation, cytokine production, and memory formation.
  • This approach shows promise for enhancing CAR T cell therapy in mesothelin-expressing solid tumors.
Keywords:
MSLN-CAR-T cellsMemory T cellsPD1/IL15Rβ switch receptorPD1/PDL1 signalingSTAT5 activationT cell exhaustion

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