Biology subjects

Haanen, J.

Publications and source records attributed to Haanen, J..

3 recordsLinked to original sources

bioRxiv2024

Tertiary lymphoid structure-related immune infiltrates in NSCLC tumor lesions correlate with low tumor-reactivity of TIL products

Adoptive transfer of tumor infiltrating lymphocytes (TIL therapy) has shown great potential for the treatment of solid cancers, including non-small cell lung cancer (NSCLC). However, not all patients benefit from this therapy, and the parameters that define the likelihood of TIL products to be tumor reactive are to date unknown. Defining prognostic markers that correlate with high level of tumor-reactivity is key for achieving better tailored immunotherapies. To determine whether the composition of immune cell infiltrates correlates with the tumor-reactivity of expanded TIL products, we employed multi-parameter flow cytometry to characterize the immune cell infiltrates from 26 early-stage, and 20 late-stage NSCLC tumor lesions. Unbiased flow cytometry analysis with Cytotree and Spearmans Rank Correlation was used to correlate immune infiltrates with the expansion rate, immune cell activation and T cell differentiation state, and the anti-tumor response of TIL products generated from the same lesions. The composition of tumor immune infiltrates was highly variable between patients, irrespective of the disease stage. High percentages of B cell infiltrates positively correlated with the presence of conventional CD4+ T cells, and an overall increase of naive T cell infiltrates. In contrast, high B cell infiltrates negatively correlated with the tumor-reactivity of expanded TIL products, as defined by cytokine production upon exposure to autologous tumor digest. Tumors with high B cell infiltrates contained IgD+BCL6+ B cells and CXCR5+BLC6+ CD4+ T cell infiltrates and an increased percentage of naive CD8+ T cells, indicative of the presence of tertiary lymphoid structures (TLS) in tumors with high B cell infiltrates. This study reveals that the composition of immune cell infiltrates in NSCLC tumors associates with the functionality of expanded TIL products from NSCLC tumor lesions. Importantly, the tumor-responsiveness of TIL products negatively correlated with the presence of TLS-associated immune infiltrates in tumors. Our finding may thus help improve patient selection for TIL therapy.

immunology↗

bioRxiv2020

PREDICTIVE IMMUNE CHECKPOINT BLOCKADE CLASSIFIERS DISTINGUISHING MONO- VERSUS COMBINATION THERAPY REQUIREMENT

Although high clinical response rates are seen for immune checkpoint blockade (ICB) treatment of metastatic melanomas, both intrinsic and acquired ICB resistance remain considerable clinical challenges1. Combination ICB (anti-PD-1 + anti-CTLA-4) shows improved patient benefit2-5, but is associated with severe adverse events and exceedingly high cost. Therefore, there is a dire need to stratify individual patients for their likelihood of responding to either anti-PD-1 or anti-CTLA-4 monotherapy, or the combination. Since it is conceivable that ICB responses are influenced by both tumor cell-intrinsic and -extrinsic factors6-9, we hypothesized that a predictive genetic classifier ought to mirror both these features. In a panel of patient-derived melanoma xenografts10 (PDX), we noted that cells derived from the human tumor microenvironment (TME) that were co-grafted with the tumor cells were naturally replaced by murine cells after the first passage. Taking advantage of the XenofilteR11 algorithm we recently developed to deconvolute human from murine RNA sequence reads from PDX10, we obtained curated human melanoma tumor cell RNA reads. These expression signals were computationally subtracted from the total RNA profiles in bulk (tumor cell + TME) melanomas from patients. We thus derived one genetic signature that is purely tumor cell-intrinsic ("InTumor"), and one that comprises tumor cell-extrinsic RNA profiles ("ExTumor"). Here we report that the InTumor signature predicts patient response to anti-PD-1, but not anti-CTLA-4 treatment. This was validated in melanoma PDX and cell lines, which confirmed that InTumorLO tumors were effectively eliminated by adoptive cell transfer of T-Cell Receptor (TCR)-matched cytotoxic T cells, whereas InTumorHI melanomas were refractory and grew out as fast as tumors challenged with unmatched T cells. In contrast, the ExTumor signature predicts patient response to anti-CTLA-4 but not anti-PD-1. Most importantly, we used the InTumor and ExTumor signatures in conjunction to generate an ICB response quadrant, which predicts clinical benefit for five independent melanoma patient cohorts treated with either mono- or combination ICB. Specifically, these signatures enable identification of patients who have a much higher chance of responding to the combination treatment than to either monotherapy (p < 0.05), as well as patients who are likely to experience little benefit from receiving anti-CTLA-4 on top of anti-PD-1 (p < 0.05). These signatures may be clinically exploited to distinguish patients who need combined PD-1 + CTLA-4 blockade from those who are likely to benefit from either anti-CTLA-4 or anti-PD-1 monotherapy.

cancer biology↗

bioRxiv2020

Secreted autotaxin through LPA suppresses chemotaxis and tumor infiltration of CD8+ T Cells

Autotaxin (ATX) is secreted by diverse cell types to produce lysophosphatidic acid (LPA) that regulates multiple biological functions via G protein-coupled receptors LPAR1-6. ATX/LPA promotes tumor cell migration and metastasis mainly via LPAR1; however, its actions in the tumor immune microenvironment remain unclear. Here, we show that ATX secreted by melanoma cells is chemorepulsive for tumor-infiltrating lymphocytes and circulating CD8+ T cells ex vivo, with ATX functioning as an LPA-producing chaperone. Mechanistically, T-cell repulsion predominantly involves G12/13-coupled LPAR6. Upon anti-cancer vaccination of tumor-bearing mice, ATX does not affect the induction of systemic T-cell responses but suppresses tumor infiltration of cytotoxic CD8+ T cells and thereby impairs tumor regression. Moreover, single-cell data from patient samples are consistent with intra-tumor ATX acting as a T-cell repellent. These studies highlight an unexpected role for the pro-metastatic ATX-LPAR axis in suppressing CD8+ T-cell infiltration to impede anti-tumor immunity, suggesting new therapeutic opportunities.

cancer biology↗