Researchers identified key differences between cancers that respond to immunotherapy and those that do not


A research project led by The University of Western Australia in collaboration with Telethon Kids Institute and 13 health research organizations has identified key differences between cancers that respond to immunotherapy and those that do not.

The breakthrough, which has the potential to improve cancer treatment, is published in the journal Science Translational Medicine.

Immunotherapy treatment works by enhancing the body’s immune response to help fight cancer.

Scientist Dr. Rachael Zemek, who completed the work as part of her Ph.D. at UWA’s National Centre for Asbestos Related Diseases and is now based at Telethon Kids Institute, said immunotherapy could result in the complete disappearance of cancer in a handful of patients, but why it worked for some people and not others was unknown.

“Through our research we found that by activating a particular immunological pathway before treatment, we could dramatically boost the response to immunotherapy treatment in mice,” Dr. Zemek said.

“We developed a unique way of analyzing cancer samples before treatment and then compared the genes between responding and non-responding cancers,” she said.

After analyzing the genes found within cancer samples, the researchers were surprised to see that even before immunotherapy, they could tell which cancers were going to respond.

Dr. Joost Lesterhuis, from UWA’s School of Biomedical Sciences and the Telethon Kids Institute, who led the research and supervised Dr. Zemek during the study, said the team then identified drugs that could increase expression of the genes to increase the response to immunotherapy treatment.

“By preparing the immune system before therapy, it can strengthen the response,” Dr. Lesterhuis said.

“This has exciting future potential to help more cancer patients benefit from immunotherapy.”

The method has not yet been tested on people with cancer who have received immunotherapy; however clinical trials could begin within the next few years.

More information: Rachael M. Zemek et al. Sensitization to immune checkpoint blockade through activation of a STAT1/NK axis in the tumor microenvironment, Science Translational Medicine (2019). DOI: 10.1126/scitranslmed.aav7816

Despite the advances made in cancer treatment, there are subsets of patients who do not respond to conventional chemotherapy treatment paradigms or who have disease-related relapse.

Recently researchers have focused on the role that the immune system plays in cancer control.

While previous conceptions of cancer were based on the proliferation of a single, clonal, disordered cell, an important hallmark of cancer is now accepted to be the evasion of cancer cells from immune destruction [1,2].

It is now appreciated that the interaction between cancer cells and immune cells within the microenvironment is the basis for cancer cell escape from immune surveillance

In an effort to address this issue, cancer immunotherapy has emerged as a treatment modality for various malignancies.

Cancer immunotherapy is based on generating strategies to exploit the mechanisms that govern the interplay between cancer cells and immune cells within the microenvironment.

This mini-review will provide background into the discovery of important biomarkers in current major cancer immunotherapy modalities including immune checkpoint blockade and chimeric antigen receptor (CAR) T cell therapy.

Additionally, we will provide an overview of existing cutting-edge methodologies used in biomarker discovery, highlight the advantages of utilizing each method, and discuss current and future directions for biomarker discovery.

Immune Checkpoint Therapy

Immune checkpoint molecules function to prevent autoimmunity and tissue damage during pathogenic infection.

These molecules are inhibitory receptors expressed on the surfaces of T cells and tumor cells, and mediate the functional interaction between these cells [3].

In a process referred to as adaptive immune resistance, engagement of immune checkpoint molecules on T cells by tumor cells suppresses the cytotoxic capacity of T cells and enables tumor cells to escape cytotoxicity [4,5].

Extrinsic T cell immune-inhibition involves the secretion of inhibitory molecules such as TGF-β, IL-10, and indoleamine 2,3-dioxyenase (IDO).

This process decreases cytotoxic T lymphocyte function, and decreases the recruitment of anti-inflammatory cells, regulatory T cells (Treg) and myeloid derived suppressor cells (MDSC) [6,7].

Evidence has emerged that cancers can be further categorized into two distinct tumor types: immunologically-ignorant and immunologically-responsive tumors [7].

Immunologically-ignorant tumors have low mutation load, are immune tolerant against self-antigens, and lack of infiltrating T cells [6].

Immunologically-responsive tumors, on the other hand, have a plethora of infiltrating T cells which in turn reflects intrinsic T cell immune-inhibition and extrinsic tumor-related T cell immunosuppression [8].

The process of T cell immune-inhibition is mediated through immune checkpoint molecule activation.

These immune checkpoint molecules include cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1), T cell immunoglobulin mucin-3 (Tim-3) and lymphocyte-activation gene 3 (LAG-3) [6,9,10].

This review will focus on the CTLA-4 and PD-1/PD-L1 checkpoints given their advanced clinical development and relevance. TIGIT (T cell immunoreceptor with Ig and ITIM domains) is an inhibitory immune checkpoint molecule that has recently emerged in the field of immunotherapy.

TIGIT is expressed on immune cells including regulatory T cells (Tregs) and natural killer (NK) cells [[11][12][13][14]].

An increased TIGIT/CD226 expression ratio on Tregs has been associated with reduced cytokine production and poor survival in multiple cancer models, including acute myeloid leukemia (AML), glioblastoma multiforme (GBM), and melanoma [[11][12][13][14]]. 

Table 1 provides a summary of the biomarkers studied that are associated with clinical response in immune checkpoint blockade of both CTLA-4 and PD-1. 

Fig. 1provides an overview regarding the mechanisms involved in regulating the functional interaction between immune cells and tumor cells. 

Table 2 provides a summary of the cancer immunotherapies approved by the United States Food and Drug Administration (FDA). 

Table 3provides a summary of the cutting-edge technologies that are currently being utilized in the discovery and validation of immunotherapeutic biomarkers.

Fig. 1
Fig. 1
Mechanisms of immune checkpoint regulation.
CTLA-4 and PD-1/PD-L1 are immune checkpoint molecules present on the surfaces of activated T cells. CTLA-4 competes for B7 ligands (CD80 and CD86) with CD28, a costimulatory molecule, and attenuate T cell proliferation and activation. When PD-1 binds to its corresponding ligand, PD-L1, on the tumor cell surface, this results in T cell exhaustion. PD-L1 expression induced on antigen-presenting cells may also suppress T-cell responses by binding to CD80 on T cells. Myeloid derived suppressor cells (MDSC) and regulatory T cells (Tregs) are key immunosuppressive cells of the immune system that promote cancer progression to limit antitumor T cell immunity through a number of contact-dependent and independent mechanisms. CTLA-4 expressed on Tregs is crucial for their suppressive activity. PD-L1+ MDSCs and PDL1+ Tregs are likely another major source of PD-L1 that inhibits T cell activation and function.

Journal information: Science Translational Medicine
Provided by University of Western Australia


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