July 25, 2024

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NKG2A Inhibition Reveals a Vulnerability in Triple-Negative Breast Cancer

Unlocking Immunotherapy’s Potential: NKG2A Inhibition Reveals a Vulnerability in Triple-Negative Breast Cancer



Unlocking Immunotherapy’s Potential: NKG2A Inhibition Reveals a Vulnerability in Triple-Negative Breast Cancer

Scientists have uncovered a vulnerability in the antigen presentation of triple-negative breast cancer (TNBC), offering a potential breakthrough in immunotherapy resistance.

The research, led by Justin M. Balko and his team at Vanderbilt University in the United States, reveals a weakness in MHC-I heterogeneity in tumors resistant to immunotherapy.

MHC-I, found on the cell surface, is responsible for presenting endogenous antigens to CD8-positive T cells, aiding in the recognition and attack of infected or abnormal cells. Disruption or dysfunction of tumor cell-specific MHC-I (tsMHC-I) is a common mechanism for evading adaptive immunity, leading to resistance to immunotherapy.

However, the study highlights that natural killer (NK) cells, comrades of CD8-positive T cells, do not rely on MHC-I for antigen presentation when attacking tumor cells.

The researchers discovered that the tumor microenvironment with MHC-I heterogeneity recruits a large number of NK cells. Targeting the inhibitory receptor NKG2A expressed by NK cells, in combination with PD-L1 inhibitors, synergistically overcomes resistance to PD-L1 inhibitor therapy. The findings were recently published in the journal “Cancer Discovery.”

Unlocking Immunotherapy's Potential: NKG2A Inhibition Reveals a Vulnerability in Triple-Negative Breast Cancer

The correlation between tsMHC-I levels and the immunotherapy outcomes in breast cancer patients had not been extensively explored before. To investigate, Balko and his team analyzed preoperative biopsy specimens from 84 metastatic TNBC patients participating in a phase II clinical trial (NCT03206203) evaluating the effectiveness of atezolizumab plus carboplatin. Results showed that combination immunotherapy and chemotherapy significantly improved progression-free survival (PFS) for patients with high tsMHC-I levels, while those with low tsMHC-I levels did not benefit additionally from introduced immunotherapy.

Unlocking Immunotherapy's Potential: NKG2A Inhibition Reveals a Vulnerability in Triple-Negative Breast Cancer

To understand how tsMHC-I affects immunotherapy outcomes, the researchers conducted single-cell analysis of tumor tissue samples from 314 patients with different breast cancer subtypes. They revealed high tsMHC-I heterogeneity in TNBC tumors. Subsequently, mouse experiments showed that the tumor microenvironment with tsMHC-I heterogeneity could recruit higher levels of NK cells in an IFN-γ-dependent manner compared to regions with uniform tsMHC-I expression.

In other words, while tsMHC-I heterogeneity may not be favorable for T cells, it provides an opportunity for NK cells to infiltrate.

To tackle TNBC tumors with tsMHC-I heterogeneity, the researchers proposed mobilizing NK cells. However, NK cells within tumors are not fully effective. Both NK cells and T cells express the inhibitory receptor NKG2A, which produces an immune inhibitory signal when binding to the HLA-E protein expressed by tumor cells. The expression of NKG2A on infiltrating NK cells and T cells in tumors significantly increased compared to normal tissues.

To address this, the researchers used an immune checkpoint inhibitor targeting NKG2A (Monalizumab) for treatment. Results from experiments on breast cancer mouse models (EMT6) showed that single-agent treatment with the NKG2A inhibitor or combined treatment with PD-L1 inhibitor did not improve the survival or inhibit tumor growth in tumor-bearing mice. However, combined therapy demonstrated a significant anti-tumor effect, with a complete response rate of 30%. Similar results were obtained with another breast cancer mouse model (E0771).

Upon testing, on the third day after treatment, mice receiving single-agent NKG2A inhibitor or combined PD-L1 inhibitor treatment showed a significant increase in infiltrating NK cell levels and enhanced cytotoxicity. However, by the seventh day of treatment, only mice receiving combined therapy maintained high levels of infiltrating NK cells in tumors. Additionally, mice receiving PD-L1 inhibitor monotherapy showed increased cytotoxicity in infiltrating T cells but not NK cells.

This indicates that inhibiting NKG2A and PD-L1 has a synergistic effect, activating T cells while awakening a large number of NK cells dormant in the tumor microenvironment with tsMHC-I heterogeneity.

Finally, the researchers evaluated the relationship between tsMHC-I levels and immune cell infiltration in TNBC patients. Results revealed a positive correlation between tsMHC-I levels and CD8-positive T cell infiltration in TNBC tumors, but no linear relationship with NK cell infiltration. Consistent with mouse experiments, tumor regions with tsMHC-I heterogeneity (tsMHC-IHET) had the highest levels of NK cell infiltration and moderate levels of CD8-positive T cell infiltration.

They defined regions with tsMHC-IHET accounting for more than 85% of the patient’s tumor tissue as having high abundance of tsMHC-I heterogeneity. They found that in patients receiving combined chemotherapy and immunotherapy, high abundance of tsMHC-I heterogeneity was closely associated with better progression-free survival, unrelated to the efficacy of chemotherapy alone. Moreover, patients with high abundance of tsMHC-I heterogeneity had a higher ratio of NK cell to T cell infiltration in tumor tissue, suggesting that targeting NKG2A may be more effective for these patients.

In summary, Justin M. Balko and his team found that tsMHC-I heterogeneity alters the pattern of immune cell infiltration. While tsMHC-I heterogeneity hinders T cells from obtaining tumor-specific antigens and exerting cytotoxic functions, it also exposes a fatal weakness by recruiting a large number of NK cells into the tumor microenvironment. This research highlights the potential of NK cells in improving the efficacy of immunotherapy.


What is NKG2A inhibition?

 
 
NKG2A (Natural Killer Group 2A) is an inhibitory receptor expressed on natural killer (NK) cells and a subset of T cells. It plays a crucial role in regulating the activity of these immune cells. NKG2A forms a heterodimeric complex with CD94 and recognizes HLA-E (Human Leukocyte Antigen-E) molecules on target cells.

The interaction between NKG2A and HLA-E serves as a checkpoint mechanism to prevent excessive activation of NK cells and T cells. When NKG2A binds to HLA-E, it delivers inhibitory signals that suppress the cytotoxic activity of NK cells and T cells. This is a natural regulatory mechanism to prevent the immune system from attacking healthy cells that express HLA-E.

In the context of cancer and immunotherapy, inhibiting NKG2A has emerged as a potential strategy to enhance the anti-tumor immune response. By blocking the inhibitory signals transmitted through NKG2A, the activity of NK cells and T cells can be unleashed, allowing them to more effectively recognize and eliminate cancer cells.

Monalizumab is one of the antibodies designed to inhibit NKG2A. It is a humanized IgG4 monoclonal antibody that specifically targets and blocks the NKG2A receptor. By doing so, it aims to relieve the inhibitory signals on NK cells and T cells, promoting their anti-tumor activity.

The combination of NKG2A inhibition with other immunotherapies, such as PD-L1 inhibitors, has shown promise in preclinical and clinical studies. In the context of the medical news you provided earlier, the researchers found that combining NKG2A inhibition with PD-L1 inhibitors had a synergistic effect in overcoming resistance to PD-L1 inhibitor therapy in MHC-I heterogeneous tumors. This combination led to improved outcomes, including increased survival and a higher rate of complete responses in experimental models.

It’s important to note that while NKG2A inhibition shows potential in certain cancer types, further research and clinical trials are needed to fully understand its efficacy, safety, and the specific contexts in which it may be most beneficial for patients. The field of cancer immunotherapy is dynamic, and ongoing research continues to explore new ways to harness the immune system to target and eliminate cancer cells.

Unlocking Immunotherapy’s Potential: NKG2A Inhibition Reveals a Vulnerability in Triple-Negative Breast Cancer


Reference:
[1] https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-23-0519/729449/NKG2A-is-a-Therapeutic-Vulnerability-in

(source:internet, reference only)

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