Biology subjects

Haanen, J. B.

Publications and source records attributed to Haanen, J. B..

3 recordsLinked to original sources

bioRxiv2021

γδ T cells are effectors of immune checkpoint blockade in mismatch repair-deficient colon cancers with antigen presentation defects

DNA mismatch repair deficient (MMR-d) cancers present an abundance of neoantigens that likely underlies their exceptional responsiveness to immune checkpoint blockade (ICB)1,2. However, MMR-d colon cancers that evade CD8+ T cells through loss of Human Leukocyte Antigen (HLA) class I-mediated antigen presentation3-6, frequently remain responsive to ICB7 suggesting the involvement of other immune effector cells. Here, we demonstrate that HLA class I-negative MMR-d cancers are highly infiltrated by {gamma}{delta} T cells. These {gamma}{delta} T cells are mainly composed of V{delta}1 and V{delta}3 subsets, and express high levels of PD-1, activation markers including cytotoxic molecules, and a broad repertoire of killer-cell immunoglobulin-like receptors (KIRs). In vitro, PD-1+ {gamma}{delta} T cells, isolated from MMR-d colon cancers, exhibited a cytolytic response towards HLA class I-negative MMR-d colon cancer cell lines and {beta}2-microglobulin (B2M)-knockout patient-derived tumor organoids (PDTOs), which was enhanced as compared to antigen presentation-proficient cells. This response was diminished after blocking the interaction between NKG2D and its ligands. By comparing paired tumor samples of MMR-d colorectal cancer patients obtained before and after dual PD-1 and CTLA-4 blockade, we found that ICB profoundly increased the intratumoral frequency of {gamma}{delta} T cells in HLA class I-negative cancers. Taken together, these data indicate that {gamma}{delta} T cells contribute to the response to ICB therapy in patients with HLA class I-negative, MMR-d colon cancers, and illustrate the potential of {gamma}{delta} T cells in cancer immunotherapy.

cancer biology↗

bioRxiv2020

T cells expanded from renal cell carcinoma are tumor-reactive but fail to produce IFN-γ, TNF-α or IL-2

Metastatic renal cell carcinoma (RCC) has a poor prognosis. Recent advances have shown beneficial responses to immune checkpoint inhibitors, such as anti-PD-1 or anti-PD-L1 antibodies. As only a subset of RCC patients respond, alternative strategies should be explored. Patients refractory to anti-PD-1 therapy may benefit from autologous tumor infiltrating lymphocyte (TIL) therapy. Even though efficient TIL expansion was reported from RCC lesions, it is not well established how many RCC TIL products are tumor-reactive, how well they produce pro-inflammatory cytokines in response to autologous tumors, and whether their response correlates with the presence of specific immune cells in the tumor lesions. We here compared the immune infiltrate composition of RCC lesions with that of autologous kidney tissue of 18 RCC patients. T cell infiltrates were increased in the tumor lesions, and CD8+ T cell infiltrates were primarily of effector memory phenotype. Nine out of 16 (56%) tested TIL products we generated were tumor-reactive, as defined by CD137 upregulation after exposure to autologous tumor digest. Tumor reactivity was found in particular in TIL products originating from tumors with a high percentage of infiltrated T cells compared to autologous kidney, and coincided with increased ex vivo CD25 expression on CD8+ T cells. Importantly, although TIL products had the capacity to produce the key effector cytokines IFN-{gamma}, TNF- or IL-2, they failed to do so in response to autologous tumor digests. In conclusion, TIL products from RCC lesions contain tumor-reactive T cells. Their lack of tumor-specific cytokine production requires further investigation of immunosuppressive factors in RCC and subsequent optimization of RCC-derived TIL culture conditions.

immunology↗

bioRxiv2018

Polyfunctional tumor-reactive T cells are effectively expanded from non-small cell lung cancers, and correlate with an immune-engaged T cell profile in situ

Non-small cell lung cancer (NSCLC) is the second most prevalent type of cancer. With the current treatment regimens, the mortality rate remains high. Therefore, better therapeutic approaches are necessary. NSCLCs generally possess many genetic mutations and are well infiltrated by T cells (TIL), making TIL therapy an attractive option. Here we show that T cells from treatment naive, stage I-IVa NSCLC tumors can effectively be isolated and expanded, with similar efficiency as from normal lung tissue. Importantly, 76% (13/17) of tested TIL products isolates from NSCLC lesions exhibited clear reactivity against primary tumor digests, with 0.5%-30% of T cells producing the inflammatory cytokine Interferon (IFN)-{gamma}. Both CD4+ and CD8+ T cells displayed tumor reactivity. The cytokine production correlated well with CD137 and CD40L expression. Furthermore, almost half (7/17) of the TIL products contained polyfunctional T cells that produced Tumor Necrosis Factor (TNF)- and/or IL-2 in addition to IFN-{gamma}, a hallmark of effective immune responses. Tumor-reactivity in the TIL products correlated with high percentages of CD103+CD69+CD8+ T cell infiltrates in the tumor lesions, with PD-1hiCD4+ T cells, and with FoxP3+CD25+CD4+ regulatory T cell infiltrates, suggesting that the composition of T cell infiltrates may predict the level of tumor reactivity. In conclusion, the effective generation of tumor-reactive and polyfunctional TIL products implies that TIL therapy will be a successful treatment regimen for NSCLC patients.

immunology↗