The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Deputy Editor-in-Chief Dr. Sjoerd H. van der Burg.
“Lymphatic-localized Treg-mregDC crosstalk limits antigen trafficking and restrains anti-tumor immunity” by Siyuan You et al
Cancer Cell (2024)
Summary:
The tumor microenvironment (TME) has a significant impact on tumor growth and immunotherapy efficacies. However, the precise cellular interactions and spatial organizations within the TME that drive these effects remain elusive. Using advanced multiplex imaging techniques, we have discovered that regulatory T cells (Tregs) accumulate around lymphatic vessels in the peripheral tumor stroma. This localized accumulation is facilitated by mature dendritic cells enriched in immunoregulatory molecules (mregDCs), which promote chemotaxis of Tregs, establishing a peri-lymphatic Treg-mregDC niche. Within this niche, mregDCs facilitate Treg activation, which in turn restrains the trafficking of tumor antigens to the draining mesenteric lymph nodes, thereby impeding the initiation of anti-tumor adaptive immune responses. Disrupting Treg recruitment to mregDCs inhibits tumor progression. Our study provides valuable insights into the organization of TME and how local crosstalk between lymphoid and myeloid cells suppresses anti-tumor immune responses.
Why this matters:
This work is important as it utilizes state of the art techniques to visualize and characterize cells in the TME, coupled to in vivo experiments to demonstrate underlying mechanisms on an important topic: How do Tregs dampen tumor immunity? Here they show that Tregs interact with migratory DC expressing checkpoint inhibitors (e.g. PDL-1), also called mregDC, that are sitting nearby the lymphatic vessels. Tregs then dampen the capacity of these dendritic cells to migrate to the lymph nodes where they were supposed to activate tumor-specific T cell immunity.
“Neoantigen-specific cytotoxic Tr1 CD4 T cells suppress cancer immunotherapy” by Hussein Sultan et al
Nature (2024)
Abstract:
CD4+ T cells can either enhance or inhibit tumour immunity. Although regulatory T cells have long been known to impede antitumour responses, other CD4+ T cells have recently been implicated in inhibiting this response. Yet, the nature and function of the latter remain unclear. Here, using vaccines containing MHC class I (MHC-I) neoantigens (neoAgs) and different doses of tumour-derived MHC-II neoAgs, we discovered that whereas the inclusion of vaccines with low doses of MHC-II-restricted peptides (LDVax) promoted tumour rejection, vaccines containing high doses of the same MHC-II neoAgs (HDVax) inhibited rejection. 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. We then documented modalities to overcome this inhibition, specifically via anti-LILRB4 blockade, using a CD8-directed IL-2 mutein, or targeted loss of cDC2/monocytes. Collectively, these data show that cytotoxic Tr1 cells, which maintain peripheral tolerance, also inhibit antitumour responses and thereby function to impede immune control of cancer.
Why this matters:
This article is highly interesting as it shows the complexity with respect to therapeutic cancer vaccines. Too high dosing for MHC class II presented antigens may lead to the activation of a specific Treg subset which subsequently impairs immunotherapy. Importantly, this may be overcome by LIRB4 blockade. It will be of interest to see if this also occurs in human trials.
“A Large-Scale Meta-Analysis Reveals Positive Feedback between Macrophages and T Cells That Sensitizes Tumors to Immunotherapy” by Jing Yang et al
Cancer Res. (2024)
Abstract:
Although considerable efforts have been dedicated to identifying predictive signatures for immune checkpoint inhibitor (ICI) treatment response, current biomarkers suffer from poor generalizability and reproducibility across different studies and cancer types. The integration of large-scale multiomics studies holds great promise for discovering robust biomarkers and shedding light on the mechanisms of immune resistance. In this study, we conducted the most extensive meta-analysis involving 3,037 ICI-treated patients with genetic and/or transcriptomics profiles across 14 types of solid tumor. The comprehensive analysis uncovered both known and novel reliable signatures associated with ICI treatment outcomes. The signatures included tumor mutational burden (TMB), IFNG and PDCD1 expression, and notably, interactions between macrophages and T cells driving their activation and recruitment. Independent data from single-cell RNA sequencing and dynamic transcriptomic profiles during the ICI treatment provided further evidence that enhanced cross-talk between macrophages and T cells contributes to ICI response. A multivariable model based on eight nonredundant signatures significantly outperformed existing models in five independent validation datasets representing various cancer types. Collectively, this study discovered biomarkers predicting ICI response that highlight the contribution of immune cell networks to immunotherapy efficacy and could help guide patient treatment.
Why this matters:
This is a highly interesting analysis as there is a new wave showing the importance of myeloid cells (neutrophils, eosinophils and macrophages) for immunotherapy. We recently published how the interplay between macrophages and T cells is important for immunotherapy to be successful and how this mechanistically works. In this paper, a huge meta-analysis is performed in order to predict checkpoint responses. The key finding is that while previous studies have linked T cell and macrophage activity to ICI responses, the findings of this study emphasize that individual T or macrophage signatures have minimal impact, whereas their interaction substantially predicts ICI response.
“Targeted therapies prime oncogene-driven lung cancers for macrophage-mediated destruction” by Kyle Vaccaro et al
J Clin Invest. (2024)
Abstract:
Macrophage immune checkpoint inhibitors, such as anti-CD47 antibodies, show promise in clinical trials for solid and hematologic malignancies. However, the best strategies to use these therapies remain unknown, and ongoing studies suggest they may be most effective when used in combination with other anticancer agents. Here, we developed an unbiased, high-throughput screening platform to identify drugs that render lung cancer cells more vulnerable to macrophage attack, and we found that therapeutic synergy exists between genotype-directed therapies and anti-CD47 antibodies. In validation studies, we found that the combination of genotype-directed therapies and CD47 blockade elicited robust phagocytosis and eliminated persister cells in vitro and maximized antitumor responses in vivo. Importantly, these findings broadly applied to lung cancers with various RTK/MAPK pathway alterations — including EGFR mutations, ALK fusions, or KRASG12C mutations. We observed downregulation of β2-microglobulin and CD73 as molecular mechanisms contributing to enhanced sensitivity to macrophage attack. Our findings demonstrate that dual inhibition of the RTK/MAPK pathway and the CD47/SIRPa axis is a promising immunotherapeutic strategy. Our study provides strong rationale for testing this therapeutic combination in patients with lung cancers bearing driver mutations.
Why this matters:
The authors’ work is interesting as it harnesses the great promise of macrophages to kill tumor cells. Macrophages are the largest population of immune cells in tumors. While CD47 blockade – to increase phagocytosis of tumor cells by macrophages – shows some promise as therapy in the clinic, its effect is modest. While tyrosine kinase inhibitors (TKIs) are usually applied to directly stop tumor cell growth, here large screens were performed to see if they could increase the efficacy of CD47 blockade to empower macrophages to phagocytose and kill tumor cells. This was the case and TKI-mediated downregulation of β2-microglobulin and CD73 were found to act as molecular mechanisms contributing to enhanced sensitivity to macrophage attack.