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"Lee, Peter P"
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B cell receptor signaling strength modulates cancer immunity
Tumor-infiltrating B cells exert antitumor effects by producing antibodies against tumor-associated antigens. Conversely, B cells may promote tumors through the production of factors that dampen antitumor immunity. In this issue of the JCI, Bing Yang, Zhen Zhang, et al. investigated the roles of B cell receptor (BCR) signaling in antitumor immunity, focusing on the role of an Asia-specific variant of human immunoglobulin G1 (IgG1) containing a Gly396 to Arg396 substitution (hIgG1-G396R) in colorectal cancer (CRC). Epidemiological analysis revealed an association between hIgG1-G396R and progression-free survival in CRC. Human samples and mouse models of CRC showed plasma cells, as opposed to B cells, infiltrating the tumor microenvironment. Notably, patients with the hIgG1-G396R variant had increased CD8+ T cells, dendritic cells, and tertiary lymphoid structure density. These findings indicate that the hIgG1-G396R variant represses tumorigenesis by enhancing B cell responses, and suggest that modulating BCR signaling could improve the efficacy of immunotherapy in cancer.
Journal Article
Connecting blood and intratumoral Treg cell activity in predicting future relapse in breast cancer
Regulatory T (T
reg
) cells play a major role in the development of an immunosuppressive tumor microenvironment. The origin of intratumoral T
reg
cells and their relationship with peripheral blood T
reg
cells remain unclear. T
reg
cells consist of at least three functionally distinct subpopulations. Here we show that peripheral blood CD45RA
−
FOXP3
hi
T
reg
cells (T
reg
II cells) are phenotypically closest to intratumoral T
reg
cells, including in their expression of CCR8. Analyses of T cell antigen receptor repertoires further support the hypothesis that intratumoral T
reg
cells may originate primarily from peripheral blood T
reg
II cells. Moreover, the signaling responsiveness of peripheral blood T
reg
II cells to immunosuppressive, T helper type 1 (T
H
1) and T helper type 2 (T
H
2) cytokines reflects intratumoral immunosuppressive potential, and predicts future relapse in two independent cohorts of patients with breast cancer. Together, our findings give important insights into the relationship between peripheral blood T
reg
cells and intratumoral T
reg
cells, and highlight cytokine signaling responsiveness as a key determinant of intratumoral immunosuppressive potential and clinical outcome.
T
reg
cells obstruct effective anticancer responses. Lee and colleagues describe a T
reg
cell biomarker signature that is strongly associated with enhanced suppression and progression of human breast cancer.
Journal Article
Human breast tumor-infiltrating CD8+ T cells retain polyfunctionality despite PD-1 expression
Functional CD8
+
T cells in human tumors play a clear role in clinical prognosis and response to immunotherapeutic interventions. PD-1 expression in T cells involved in chronic infections and tumors such as melanoma often correlates with a state of T-cell exhaustion. Here we interrogate CD8
+
tumor-infiltrating lymphocytes (TILs) from human breast and melanoma tumors to explore their functional state. Despite expression of exhaustion hallmarks, such as PD-1 expression, human breast tumor CD8
+
TILs retain robust capacity for production of effector cytokines and degranulation capacity. In contrast, melanoma CD8
+
TILs display dramatic reduction of cytokine production and degranulation capacity. We show that CD8
+
TILs from human breast tumors can potently kill cancer cells via bi-specific antibodies. Our data demonstrate that CD8
+
TILs in human breast tumors retain polyfunctionality, despite PD-1 expression, and suggest that they may be harnessed for effective immunotherapies.
Expression of the checkpoint molecule programmed cell death protein 1 (PD-1) is considered a marker of T cells exhaustion. Here the authors show that CD8T cells isolated from breast cancer patients are perfectly functional despite PD-1 expression while those isolated from melanoma patients are not.
Journal Article
On the mechanism of long-range orientational order of fibroblasts
Long-range alignment ordering of fibroblasts have been observed in the vicinity of cancerous tumors and can be recapitulated with in vitro experiments. However, the mechanisms driving their ordering are not understood. Here, we show that local collision-driven nematic alignment interactions among fibroblasts are insufficient to explain observed long-range alignment. One possibility is that there exists another orientation field coevolving with the cells and reinforcing their alignment. We propose that this field reflects the mechanical cross-talk between the fibroblasts and the underlying fibrous material on which they move. We show that this long-range interaction can give rise to high nematic order and to the observed patterning of the cancer microenvironment.
Journal Article
Modulation of P2X4/P2X7/Pannexin-1 sensitivity to extracellular ATP via Ivermectin induces a non-apoptotic and inflammatory form of cancer cell death
Overexpression of P2X7 receptors correlates with tumor growth and metastasis. Yet, release of ATP is associated with immunogenic cancer cell death as well as inflammatory responses caused by necrotic cell death at sites of trauma or ischemia-reperfusion injury. Using an FDA-approved anti-parasitic agent Ivermectin as a prototype agent to allosterically modulate P2X4 receptors, we can switch the balance between the dual pro-survival and cytotoxic functions of purinergic signaling in breast cancer cells. This is mediated through augmented opening of the P2X4/P2X7-gated Pannexin-1 channels that drives a mixed apoptotic and necrotic mode of cell death associated with activation of caspase-1 and is consistent with pyroptosis. We show that cancer cell death is dependent on ATP release and death signals downstream of P2X7 receptors that can be reversed by inhibition of NADPH oxidases-generated ROS, Ca
2+
/Calmodulin-dependent protein kinase II (CaMKII) or mitochondrial permeability transition pore (MPTP). Ivermectin induces autophagy and release of ATP and HMGB1, key mediators of inflammation. Potentiated P2X4/P2X7 signaling can be further linked to the ATP rich tumor microenvironment providing a mechanistic explanation for the tumor selectivity of purinergic receptors modulation and its potential to be used as a platform for integrated cancer immunotherapy.
Journal Article
Tumor draining lymph nodes connected to cold triple-negative breast cancers are characterized by Th2-associated microenvironment
Tumor draining lymph nodes (TDLN) represent a key component of the tumor-immunity cycle. There are few studies describing how TDLNs impact lymphocyte infiltration into tumors. Here we directly compare tumor-free TDLNs draining “cold” and “hot” human triple negative breast cancers (TDLN
Cold
and TDLN
Hot
). Using machine-learning-based self-correlation analysis of immune gene expression, we find unbalanced intranodal regulations within TDLN
Cold
. Two gene pairs (
TBX21
/
GATA3
-
CXCR1
) with opposite correlations suggest preferential priming of T helper 2 (Th2) cells by mature dendritic cells (DC) within TDLN
Cold
. This is validated by multiplex immunofluorescent staining, identifying more mature-DC-Th2 spatial clusters within TDLN
Cold
versus TDLN
Hot
. Associated with this Th2 priming preference, more IL4 producing mast cells (MC) are found within sinus regions of TDLN
Cold
. Downstream, Th2-associated fibrotic TME is found in paired cold tumors with increased Th2/T-helper-1-cell (Th1) ratio, upregulated fibrosis growth factors, and stromal enrichment of cancer associated fibroblasts. These findings are further confirmed in a validation cohort and public genomic data. Our results reveal a potential role of IL4
+
MCs within TDLNs, associated with Th2 polarization and reduced immune infiltration into tumors.
Triple-negative breast cancers are aggressive tumours, but their prognosis is critically determined by the immune cell activity within the microenvironment, with the more inflamed, hot milieu predicting better prognosis. Here authors show that the tumour draining lymph nodes, even if not invaded by the tumours, reflect the difference between the cold and hot tumours via differential Th2 polarization.
Journal Article
Ligand discrimination in immune cells: Signal processing insights into immune dysfunction in ER+ breast cancer
Prior studies have shown that approximately 40% of estrogen receptor positive (ER+) breast cancer (BC) patients harbor immune signaling defects in their blood at diagnosis, and the presence of these defects predicts overall survival. Therefore, it is of interest to quantitatively characterize and measure signaling errors in immune signaling systems in these patients. Here we propose a novel approach combining communication theory and signal processing concepts to model ligand discrimination in immune cells in the peripheral blood. We use the model to measure the specificity of ligand discrimination in the presence of molecular noise by estimating the probability of error, which is the probability of making a wrong ligand identification. We apply our model to the JAK/STAT signaling pathway using high dimensional spectral flow cytometry measurements of transcription factors, including phosphorylated STATs and SMADs, in immune cells stimulated with several cytokines (IFNγ, IL-2, IL-6, IL-4, and IL-10) from 19 ER+ breast cancer patients and 32 healthy controls. In addition, we apply our model to 10 healthy donor samples treated with a clinically approved JAK1/2 inhibitor. Our results show reduced ligand identification accuracy and higher levels of molecular noise in BC patients as compared to healthy controls, which may indicate altered immune signaling and the potential for immune cell dysfunction in these patients. Moreover, the inhibition of JAK1/2 produces a unique pattern of signaling dysfunction, inducing increased ligand detection error rates and reduced signal-to-noise ratios for most immune cell subtypes. These results suggest a means to improve the use of signaling kinase inhibitor therapies by identifying patients with favorable ligand discrimination specificity profiles in their immune cells.
Journal Article
PD-L1 blockade restores CAR T cell activity through IFN-γ-regulation of CD163+ M2 macrophages
BackgroundThe immune suppressive tumor microenvironment (TME) that inhibits T cell infiltration, survival, and antitumor activity has posed a major challenge for developing effective immunotherapies for solid tumors. Chimeric antigen receptor (CAR)-engineered T cell therapy has shown unprecedented clinical response in treating patients with hematological malignancies, and intense investigation is underway to achieve similar responses with solid tumors. Immunologically cold tumors, including prostate cancers, are often infiltrated with abundant tumor-associated macrophages (TAMs), and infiltration of CD163+ M2 macrophages correlates with tumor progression and poor responses to immunotherapy. However, the impact of TAMs on CAR T cell activity alone and in combination with TME immunomodulators is unclear.MethodsTo model this in vitro, we utilized a novel co-culture system with tumor cells, CAR T cells, and polarized M1 or M2 macrophages from CD14+ peripheral blood mononuclear cells collected from healthy human donors. Tumor cell killing, T cell activation and proliferation, and macrophage phenotypes were evaluated by flow cytometry, cytokine production, RNA sequencing, and functional blockade of signaling pathways using antibodies and small molecule inhibitors. We also evaluated the TME in humanized mice following CAR T cell therapy for validation of our in vitro findings.ResultsWe observed inhibition of CAR T cell activity with the presence of M2 macrophages, but not M1 macrophages, coinciding with a robust induction of programmed death ligand-1 (PD-L1) in M2 macrophages. We observed similar PD-L1 expression in TAMs following CAR T cell therapy in the TME of humanized mice. PD-L1, but not programmed cell death protein-1, blockade in combination with CAR T cell therapy altered phenotypes to more M1-like subsets and led to loss of CD163+ M2 macrophages via interferon-γ signaling, resulting in improved antitumor activity of CAR T cells.ConclusionThis study reveals an alternative mechanism by which the combination of CAR T cells and immune checkpoint blockade modulates the immune landscape of solid tumors to enhance therapeutic efficacy of CAR T cells.
Journal Article
Warburg Effect Is a Cancer Immune Evasion Mechanism Against Macrophage Immunosurveillance
Evasion of immunosurveillance is critical for cancer initiation and development. The expression of “don’t eat me” signals protects cancer cells from being phagocytosed by macrophages, and the blockade of such signals demonstrates therapeutic potential by restoring the susceptibility of cancer cells to macrophage-mediated phagocytosis. However, whether additional self-protective mechanisms play a role against macrophage surveillance remains unexplored. Here, we derived a macrophage-resistant cancer model from cells deficient in the expression of CD47, a major “don’t eat me” signal, via a macrophage selection assay. Comparative studies performed between the parental and resistant cells identified self-protective traits independent of CD47, which were examined with both pharmacological or genetic approaches in in vitro phagocytosis assays and in vivo tumor models for their roles in protecting against macrophage surveillance. Here we demonstrated that extracellular acidification resulting from glycolysis in cancer cells protected them against macrophage-mediated phagocytosis. The acidic tumor microenvironment resulted in direct inhibition of macrophage phagocytic ability and recruitment of weakly phagocytic macrophages. Targeting V-ATPase which transports excessive protons in cancer cells to acidify extracellular medium elicited a pro-phagocytic microenvironment with an increased ratio of M1-/M2-like macrophage populations, therefore inhibiting tumor development and metastasis. In addition, blockade of extracellular acidification enhanced cell surface exposure of CD71, targeting which by antibodies promoted cancer cell phagocytosis. Our results reveal that extracellular acidification due to the Warburg effect confers immune evasion ability on cancer cells. This previously unrecognized role highlights the components mediating the Warburg effect as potential targets for new immunotherapy harnessing the tumoricidal capabilities of macrophages.
Journal Article