аналитика - Immunology - # Neoantigen-specific Cytotoxic Tr1 Cells Inhibit Antitumor Immunity

Cytotoxic Tr1 CD4 T Cells Suppress Cancer Immunotherapy by Targeting Tumor-Specific Neoantigens

Q: How can the selective killing of cDC1s by Tr1 cells be leveraged to enhance cancer immunotherapy?

The selective killing of cDC1s by Tr1 cells presents a unique opportunity to enhance cancer immunotherapy by targeting this specific interaction. By understanding that HDVax-induced Tr1 cells are responsible for the inhibition of antitumor responses through the elimination of MHC-II tumor antigen-presenting cDC1s, we can develop strategies to disrupt this process. One approach could involve developing therapies that block the cytotoxic activity of Tr1 cells specifically towards cDC1s, thereby preserving the population of cDC1s within tumors. This preservation of cDC1s would lead to increased antigen presentation and activation of effector T cells, ultimately enhancing the immune response against the tumor. Additionally, utilizing techniques to selectively deplete or inhibit the generation of Tr1 cells in response to HDVax could prevent the suppression of cDC1s and promote a more robust antitumor immune response.

Q: What are the potential limitations or unintended consequences of targeting LILRB4 to overcome Tr1-mediated suppression of antitumor immunity?

While targeting LILRB4 to overcome Tr1-mediated suppression of antitumor immunity shows promise, there are potential limitations and unintended consequences that need to be considered. One limitation is the specificity of targeting LILRB4, as this receptor may have important regulatory functions beyond its role in Tr1 cell-mediated suppression. Blocking LILRB4 could lead to off-target effects or unintended immune dysregulation, impacting the overall immune response. Additionally, the long-term effects of LILRB4 blockade on immune homeostasis and potential autoimmune reactions need to be thoroughly evaluated. Furthermore, the development of resistance mechanisms or compensatory pathways in response to LILRB4 targeting could limit the effectiveness of this approach over time. Careful consideration of these factors is essential to ensure the safety and efficacy of targeting LILRB4 in cancer immunotherapy.

Q: Given the dual role of CD4+ T cells in both promoting and inhibiting tumor immunity, how can we better harness the beneficial functions of CD4+ T cells while mitigating their suppressive effects in the context of cancer immunotherapy?

To better harness the beneficial functions of CD4+ T cells while mitigating their suppressive effects in cancer immunotherapy, a multifaceted approach is required. One strategy is to selectively target and expand tumor-specific effector CD4+ T cells that promote antitumor immunity while minimizing the activation of regulatory CD4+ T cell subsets like Tr1 cells. This can be achieved through personalized vaccine strategies that focus on inducing and amplifying effector CD4+ T cell responses against tumor-specific antigens. Additionally, combination therapies that target multiple checkpoints, such as PD-1 and LILRB4, can help overcome the inhibitory signals mediated by suppressive CD4+ T cell subsets. Furthermore, modulating the tumor microenvironment to favor the recruitment and activation of effector CD4+ T cells, while inhibiting the suppressive mechanisms of regulatory CD4+ T cells, can enhance the overall antitumor immune response. By carefully balancing the activation and regulation of CD4+ T cell subsets, we can optimize cancer immunotherapy outcomes and improve patient responses.

Основные понятия

Cytotoxic Tr1 CD4 T cells, induced by high-dose MHC-II neoantigen vaccines, suppress tumor rejection by selectively killing MHC-II tumor antigen-presenting type 1 conventional dendritic cells.

Аннотация

The article investigates the role of CD4+ T cells in modulating tumor immunity. It was found that while low-dose MHC-II neoantigen vaccines (LDVax) promoted tumor rejection, high-dose vaccines (HDVax) inhibited this response. Further characterization revealed that HDVax induced a population of type 1 regulatory T (Tr1) cells that expressed IL-10, granzyme B, perforin, CCL5, and LILRB4. These tumor-specific Tr1 cells suppressed tumor rejection induced by anti-PD1, LDVax, or adoptively transferred tumor-specific effector T cells.

Mechanistically, the HDVax-induced Tr1 cells selectively killed MHC-II tumor antigen-presenting type 1 conventional dendritic cells (cDC1s), leading to low numbers of cDC1s in the tumor. The authors then identified strategies to overcome this inhibition, such as anti-LILRB4 blockade, using a CD8-directed IL-2 mutein, or targeted depletion of cDC2/monocytes.

These findings demonstrate that cytotoxic Tr1 cells, which normally maintain peripheral tolerance, can also inhibit antitumor immune responses and impede cancer immunotherapy.

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www.nature.com

Статистика

Low-dose MHC-II neoantigen vaccines (LDVax) promoted tumor rejection, while high-dose vaccines (HDVax) inhibited this response.
HDVax induced a population of type 1 regulatory T (Tr1) cells that expressed IL-10, granzyme B, perforin, CCL5, and LILRB4.
Tumor-specific Tr1 cells suppressed tumor rejection induced by anti-PD1, LDVax, or adoptively transferred tumor-specific effector T cells.
HDVax-induced Tr1 cells selectively killed MHC-II tumor antigen-presenting type 1 conventional dendritic cells (cDC1s), leading to low numbers of cDC1s in the tumor.

Цитаты

"Characterization of the inhibitory cells induced by HDVax identified them as type 1 regulatory T (Tr1) cells expressing IL-10, granzyme B, perforin, CCL5 and LILRB4."
"Tumour-specific Tr1 cells suppressed tumour rejection induced by anti-PD1, LDVax or adoptively transferred tumour-specific effector T cells."
"Mechanistically, HDVax-induced Tr1 cells selectively killed MHC-II tumour antigen-presenting type 1 conventional dendritic cells (cDC1s), leading to low numbers of cDC1s in tumours."

Ключевые выводы из

Neoantigen-specific cytotoxic Tr1 CD4 T cells suppress cancer immunotherapy - Nature

by Hussein Sult... в www.nature.com 07-24-2024

https://www.nature.com/articles/s41586-024-07752-y

Neoantigen-specific cytotoxic Tr1 CD4 T cells suppress cancer immunotherapy - Nature

Дополнительные вопросы

How can the selective killing of cDC1s by Tr1 cells be leveraged to enhance cancer immunotherapy?

The selective killing of cDC1s by Tr1 cells presents a unique opportunity to enhance cancer immunotherapy by targeting this specific interaction. By understanding that HDVax-induced Tr1 cells are responsible for the inhibition of antitumor responses through the elimination of MHC-II tumor antigen-presenting cDC1s, we can develop strategies to disrupt this process. One approach could involve developing therapies that block the cytotoxic activity of Tr1 cells specifically towards cDC1s, thereby preserving the population of cDC1s within tumors. This preservation of cDC1s would lead to increased antigen presentation and activation of effector T cells, ultimately enhancing the immune response against the tumor. Additionally, utilizing techniques to selectively deplete or inhibit the generation of Tr1 cells in response to HDVax could prevent the suppression of cDC1s and promote a more robust antitumor immune response.

What are the potential limitations or unintended consequences of targeting LILRB4 to overcome Tr1-mediated suppression of antitumor immunity?

While targeting LILRB4 to overcome Tr1-mediated suppression of antitumor immunity shows promise, there are potential limitations and unintended consequences that need to be considered. One limitation is the specificity of targeting LILRB4, as this receptor may have important regulatory functions beyond its role in Tr1 cell-mediated suppression. Blocking LILRB4 could lead to off-target effects or unintended immune dysregulation, impacting the overall immune response. Additionally, the long-term effects of LILRB4 blockade on immune homeostasis and potential autoimmune reactions need to be thoroughly evaluated. Furthermore, the development of resistance mechanisms or compensatory pathways in response to LILRB4 targeting could limit the effectiveness of this approach over time. Careful consideration of these factors is essential to ensure the safety and efficacy of targeting LILRB4 in cancer immunotherapy.

Given the dual role of CD4+ T cells in both promoting and inhibiting tumor immunity, how can we better harness the beneficial functions of CD4+ T cells while mitigating their suppressive effects in the context of cancer immunotherapy?

To better harness the beneficial functions of CD4+ T cells while mitigating their suppressive effects in cancer immunotherapy, a multifaceted approach is required. One strategy is to selectively target and expand tumor-specific effector CD4+ T cells that promote antitumor immunity while minimizing the activation of regulatory CD4+ T cell subsets like Tr1 cells. This can be achieved through personalized vaccine strategies that focus on inducing and amplifying effector CD4+ T cell responses against tumor-specific antigens. Additionally, combination therapies that target multiple checkpoints, such as PD-1 and LILRB4, can help overcome the inhibitory signals mediated by suppressive CD4+ T cell subsets. Furthermore, modulating the tumor microenvironment to favor the recruitment and activation of effector CD4+ T cells, while inhibiting the suppressive mechanisms of regulatory CD4+ T cells, can enhance the overall antitumor immune response. By carefully balancing the activation and regulation of CD4+ T cell subsets, we can optimize cancer immunotherapy outcomes and improve patient responses.