serial-killing-assay-using-longitudinal-impedance-based-tumor-cell

Serial Killing Assay Using Longitudinal Impedance-Based Tumor Cell Viability Measurement - A Useful Method to Assess T Cell Performance

Chimeric antigen receptor (CAR) cell therapy has revolutionized the treatment of specific hematologic malignancies. However, a significant portion of ...

LMU University Hospital

In many situations, the therapeutic efficacy of CAR T cells is limited due to immune suppression and poor persistence. Immunostimulatory fusion protein (IFP) constructs have been advanced as a tool to convert suppressive signals into stimulation and thus promote the persistence of T cells, but no universal IFP design has been established so far. We now took advantage of a PD-1-CD28 IFP as a clinically relevant structure to define key determinants of IFP activity.

Rational design of PD-1-CD28 immunostimulatory fusion proteins for CAR T cell therapy.

Cancer-specific TCF1 stem-like CD8 T cells can drive protective anticancer immunity through expansion and effector cell differentiation; however, this response is dysfunctional in tumours. Current cancer immunotherapies can promote anticancer responses through TCF1 stem-like CD8 T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1CD8 T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE) restricts the proliferative expansion and effector differentiation of TCF1CD8 T cells within tumours, which promotes cancer immune escape. PGE does not affect the priming of TCF1CD8 T cells in draining lymph nodes. PGE acts through EP and EP (EP/EP) receptor signalling in CD8 T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1 tumour-infiltrating CD8 T lymphocytes (TILs). Ablation of EP/EP signalling in cancer-specific CD8 T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE-mediated inhibition of TCF1 TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1 TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE-EP/EP axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.

PGE limits effector expansion of tumour-infiltrating stem-like CD8 T cells.

The success of targeted therapies for hematological malignancies has heralded their potential as both salvage treatment and early treatment lines, reducing the need for high-dose, intensive, and often toxic chemotherapeutic regimens. For young patients with classic Hodgkin lymphoma (cHL), immunotherapies provide the possibility to lessen long-term, treatment-related toxicities. However, suitable therapeutic targets are lacking. By integrating single-cell dissection of the tumor landscape and an in-depth, single-cell-based off-tumor antigen prediction, we identify CD86 as a promising therapeutic target in cHL. CD86 is highly expressed on Hodgkin and Reed-Sternberg cancer cells and cHL-specific tumor-associated macrophages. We reveal CD86-CTLA-4 as a key suppressive pathway in cHL, driving T-cell exhaustion. Cellular therapies targeting CD86 had extraordinary efficacy in vitro and in vivo and were safe in immunocompetent mouse models without compromising bacterial host defense in sepsis models. Our results prove the potential value of anti-CD86 immunotherapies for treating cHL.

Dissection of single-cell landscapes for the development of chimeric antigen receptor T cells in Hodgkin lymphoma.

The Immunotherapy of Cancer (ITOC) meeting is an international conference providing a platform for immuno-oncologists worldwide to present and discuss their research and newest findings. Being held in Munich annually, the 11th edition took place in April 2025 and saw broad discussions about new concepts in the field of immuno-oncology, mixed with exciting clinical results but also with a glimpse back into the past. This was mirrored by the lifetime achievement award, given to  for his groundbreaking work on the immune surveillance of cancer. ITOC11 impressively showcase how far immuno-oncology has come in a conference extending from the discipline's very beginnings up to some of the most exciting new findings in the field of cancer immunology. The conference has demonstrated that tumor immunology is not only about cancer and immune cells, but extends far beyond.

Article	Year
Rational design of PD-1-CD28 immunostimulatory fusion proteins for CAR T cell therapy. British journal of cancer\| PubMed ID: 37400680	2023
PGE limits effector expansion of tumour-infiltrating stem-like CD8 T cells. Nature\| PubMed ID: 38658748	2024
Dissection of single-cell landscapes for the development of chimeric antigen receptor T cells in Hodgkin lymphoma. Blood\| PubMed ID: 40178843	2025
11th Immunotherapy of Cancer conference (ITOC): A meeting report. Human vaccines & immunotherapeutics\| PubMed ID: 40679247	2025

Stefanos Michaelides

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