How do immune cells detect and respond to cancer cell mutations?

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How do immune cells detect and respond to cancer cell mutations?

How do immune cells detect and respond to cancer cell mutations? UC study provides latest anti-cancer strategy

Neoantigens are peptides derived from non-synonymous mutations presented by human leukocyte antigens (HLA), which are recognized by anti-tumor T cells.

Extensive HLA allelic diversity and limited clinical samples limit the study of neoantigen-targeted T cell responses during patient therapy.

For the first time, a team of researchers at UCLA Jonsson Comprehensive Cancer Center has identified and analyzed the steps by which immune cells “see” and respond to cancer cells, suggesting that certain treatments may be effective for some patients.

But it offers insight into why it didn’t work in other patients . The research paper “Neoantigen-targeted CD8 T cell responses with PD-1 blockade therapy+” was published in the well-known journal “Nature”.

How do immune cells detect and respond to cancer cell mutations?
https://www.nature.com/articles/s41586-023-05787-1

Unveiling the veil of resistance to PD-1/PD-L1 therapy

Using advanced genetic techniques, researchers have obtained an unprecedented look at the immune response of metastatic melanoma patients treated with anti-PD-1 “checkpoint inhibitor” immunotherapy.

This technology can identify and isolate T cells that respond to cancer cell mutations (that is, those cells that can recognize neoE) from blood and tumors, and analyze the sequence of mutant proteins recognized by them, so scientists can obtain cancer cells in patients.

Information such as the type of mutation, the type and number of T cells that produce anti-tumor responses .

Cancer cells often evade the immune system, although immune cells called T cells have the ability to detect mutations in cancer cells and eliminate them, leaving normal cells unharmed.

Checkpoint inhibitors are designed to increase the ability of T cells to recognize and attack cancer cells.

How do immune cells detect and respond to cancer cell mutations?
Procedure for isolating neoantigen-specific T cells from patient tumors

Dr Antoni Ribas said: ” With this technology, we can know exactly how the immune system in a cancer patient distinguishes cancer cells from normal cells in the body .”

The study found

Of the 11 patients studied, seven responded to PD-1 blockade; four did not. The number of mutations in the tumors ranged from 3,507 to 31.

Despite this wide range, the number of mutations observed in tumor-reactive T cells ranged from 13 to 1.

Among patients who gained clinical benefit from treatment, responses were diverse, with 61 to 7 different mutation-specific T cells isolated in blood and tumors.

In contrast, in patients who did not respond to treatment, the researchers found only 14 to two distinct T cells.

Furthermore, in patients who responded to treatment, the researchers were able to isolate tumor-reactive T cells from the blood and tumor throughout treatment, but in patients who did not respond, T cells were not detected repeatedly.

Nonetheless, the study demonstrates that immune receptors from T cells isolated from all patients, reactive or not, redirect immune cells specific to tumors, resulting in antitumor activity .

” This is an important step forward in our understanding of what T cell responses ‘see’ in tumors and how they change over time as they circulate in the tumor and in the blood. A deeper understanding of how T cell responses clear metastatic tumor masses will help We design better treatments and engineer T cells to mimic them in a variety of ways .”

—Dr. Cristina Puig-Saus

New strategy to fight resistance to immunotherapy

The findings show that when immunotherapy is effective, patients develop a diverse repertoire of T cells that target a small subset of mutations.

These responding T cells expand and mutate in the blood and tumor during treatment.

Nonresponders also had T cell responses targeting a small number of mutations in the tumor, but these immune responses were less diverse and did not amplify during treatment.

“This study shows that in patients who do not respond to therapy, the anti-tumor T cell response is still stimulated,” said Dr. Cristina Puig-Saus, the paper’s first author. It recognizes the mutated T cell receptor (TCR) for analysis, and genetically modifies a large number of T cells based on the obtained information, so that these cells can specifically recognize the patient’s tumor. Finally, these cells are expanded in vitro and infused back into the patient’s body to treat patients.”

In conclusion, this study deepens our understanding of T cells against metastatic tumors, which will help us to mimic this natural anti-tumor response in vivo through genetic engineering and other methods to design more effective treatments against drug resistance .

References:
https://www.nature.com/articles/s41586-023-05787-1
https://www.uclahealth.org/news/