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Cancer Immune Surveillance and Therapeutic Targeting

SCIENTIFIC OBJECTIVES

Major advances in immunotherapy, particularly those targeting T lymphocytes, have led to significant progress in cancer treatment. Nevertheless, the clinical efficacy of these approaches remains variable. In addition, T lymphocytes are not autonomous in their effector functions and are closely dependent on cells of the innate immune system. In this context, our team’s work is part of a broader effort to place innate immunity at the center of immuno-oncology strategies.

The research conducted by the team aims to characterize the mechanisms by which innate immune cells (i) detect precancerous lesions and (ii) collaborate with T and B lymphocytes to control so-called “immuno-active” tumors. As true sentinels of the immune system, innate immune cells represent the majority of immune cells infiltrating solid tumors and therefore emerge as strategic and promising targets for the development of new immunotherapeutic approaches.

Our central hypothesis is that identifying the mechanisms of innate detection of cells undergoing malignant transformation, as well as analyzing the role of innate immune cells in the control of established tumors, will pave the way for:

  • new immunoprevention strategies at the precancerous stage or prior to relapse;
  • innovative therapeutic strategies at advanced stages, in combination with current immunotherapies targeting T lymphocytes.

RESEARCH AXES

The work of the CISTAR team is based on fundamental and exploratory research structured around two complementary research axes:

Axis 1 – Mechanisms of innate immune surveillance of precancerous lesions

Immune surveillance plays a key role at the early stages of carcinogenesis, and the transition from a precancerous state to invasive cancer represents a critical step in tumor development through immune evasion. However, the innate immune mechanisms involved in the recognition and elimination of precancerous cells remain largely unknown. Within this axis, we aim to identify and characterize innate detection mechanisms that are active at precancerous stages and potentially bypassed or inhibited in established tumors. This work is expected to lead to the emergence of new concepts and the development of innovative preventive or therapeutic strategies based on innate immunity, in order to intercept cancer initiation or progression.

To this end, we leverage unique human clinical contexts that allow access to fresh or fixed tissues from precancerous lesions:

  • colorectal polyps
  • STIC lesions (Serous Tubal Intraepithelial Carcinoma) in ovarian cancer
  • atypical ductal hyperplasia (ADH) in breast cancer

We also develop and use complementary experimental models of tumorigenesis, including genetically engineered mouse models as well as innovative in vitro models (organoids, etc.).

 

Axis 2 – Mechanisms of innate immune control of established tumors

The second axis takes advantage of rare but highly informative clinical situations, namely so-called “immuno-active” tumors, which are characterized by a spontaneous and effective immune response. We focus in particular on:

  • tumors associated with paraneoplastic neurological syndromes
  • cancers associated with spontaneous regression, such as low-risk neuroblastoma

These tumors are distinguished by strong infiltration of T and B lymphocytes and dendritic cells, often functionally organized into tertiary lymphoid structures, as well as the local production of antibody-secreting plasma cells, reflecting a local and antigen-specific immune response. However, the mechanisms by which innate immune cells promote this antitumor response and contribute to tumor control remain largely unexplored.

Through an in-depth analysis of the cooperation between innate and adaptive immune systems in these contexts, we aim to identify new targets and immunotherapeutic strategies, particularly for patients who are resistant to current treatments.

 

TEAM ORGANIZATIONAL CHART

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Main fundings

Université Claude Bernard Lyon I
Institut National du Cancer (INCa)
Association pour la Recherche sur le Cancer (ARC)
Ligue Contre le Cancer
Agence Nationale pour la Recherche (ANR)
Laboratoire d’Excellence (LabEx) DevWeCan (Grand Emprunt)
Fondation pour la Recherche Médicale (FRM)

Fondation Bristol Myers Squibb (BMS)

AstraZeneca

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Publications