Tumor-specific MHC-II expression drives a unique pattern of resistance to immunotherapy via LAG-3/FCRL6 engagement

Johnson, Douglas B.; Nixon, Mellissa J.; Wang, Yu; Wang, Daniel; Castellanos, Emily; Estrada, Mónica Valéria; Ericsson-Gonzalez, Paula I.; Cote, Candace H.; Salgado, Roberto; Sánchez, Violeta; Dean, Phillip T.; Opalenik, Susan R.; Schreeder, Daniel M.; Rimm, David L.; Kim, Ju Young; Bordeaux, Jennifer; Loi, Sherene; Horn, Leora; Sanders, Melinda E.; Ferrell, P. Brent; Xu, Yaomin; Sosman, Jeffrey A.; Davis, Randall S.; Balko, Justin M.

doi:10.1172/jci.insight.120360

Cited by 133 publications

(119 citation statements)

References 58 publications

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“…An increasing number of studies are linking PD‐1/LAG‐3 co‐expression in T cells to resistance to anti‐PD‐L1/PD‐1 therapies (Mishra et al , ; Huang et al , ; Williams et al , ; Johnson et al , ). Our study prompts the clinical evaluation of patients with systemic CD4 T‐cell dysfunctionality by PD‐1/LAG‐3 dual‐blockade strategies.…”

Section: Discussionmentioning

confidence: 99%

Functional systemic CD 4 immunity is required for clinical responses to PD ‐L1/ PD ‐1 blockade therapy

et al. 2019

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The majority of lung cancer patients progressing from conventional therapies are refractory to PD ‐L1/ PD ‐1 blockade monotherapy. Here, we show that baseline systemic CD 4 immunity is a differential factor for clinical responses. Patients with functional systemic CD 4 T cells included all objective responders and could be identified before the start of therapy by having a high proportion of memory CD 4 T cells. In these patients, CD 4 T cells possessed significant proliferative capacities, low co‐expression of PD ‐1/ LAG ‐3 and were responsive to PD ‐1 blockade ex vivo and in vivo . In contrast, patients with dysfunctional systemic CD 4 immunity did not respond even though they had lung cancer‐specific T cells. Although proficient in cytokine production, CD 4 T cells in these patients proliferated very poorly, strongly co‐upregulated PD ‐1/ LAG ‐3, and were largely refractory to PD ‐1 monoblockade. CD 8 immunity only recovered in patients with functional CD 4 immunity. T‐cell proliferative dysfunctionality could be reverted by PD ‐1/ LAG ‐3 co‐blockade. Patients with functional CD 4 immunity and PD ‐L1 tumor positivity exhibited response rates of 70%, highlighting the contribution of CD 4 immunity for efficacious PD ‐L1/ PD ‐1 blockade therapy.

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Section: Discussionmentioning

confidence: 99%

Functional systemic CD 4 immunity is required for clinical responses to PD ‐L1/ PD ‐1 blockade therapy

et al. 2019

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“…Both CD4 and CD8 dysfunctionality in G2 patients could be reverted ex vivo by PD-1/LAG-3 coblockade. An increasing number of studies are linking PD-1/LAG-3 co-expression in T cells to resistance to anti-PD-L1/PD-1 therapies (26)(27)(28)(29). Our study suggests that patients with dysfunctional CD4 immunity should undergo alternative treatments to recover CD4 immunity and enhance CD8 T cell functionality.…”

Section: Discussionmentioning

confidence: 78%

Functional systemic CD4 immunity is a differential factor for clinical responses to PD-L1/PD-1 blockade therapy in lung cancer

Zuazo

Arasanz

Fernández-Hinojal

et al. 2018

Preprint

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The majority of lung cancer patients progressing from conventional therapies are refractory to PD-L1/PD-1 blockade monotherapy. Here we show that baseline systemic CD4 immunity is a differential factor for clinical responses. Patients with functional systemic CD4 T cells included all objective responders and could be identified before the start of therapy by having a high proportion of memory CD4 T cells. In these patients CD4 T cells possessed significant proliferative capacities, low co-expression of PD-1/LAG-3 and were responsive to PD-1 blockade ex vivo and in vivo. In contrast, patients with dysfunctional systemic CD4 immunity did not respond even though they had lung cancer-specific CD4 and CD8 T cells. CD4 T cells in these patients proliferated very poorly, strongly co-upregulated PD-1/LAG-3, and were largely refractory to PD-1 monoblockade. CD8 immunity only recovered in patients with functional CD4 immunity. T cell dysfunctionality was caused by PD-1/LAG-3 coexpression, and could be reverted by co-blockade. Patients with functional CD4 immunity and PD-L1 tumor positivity exhibited response rates of 70%, highlighting the contribution of CD4 immunity for efficacious PD-L1/PD-1 blockade therapy. Running title: CD4 T cells as major regulators of immune checkpoint therapy

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“…FCRL6 possess an intracellular immunoreceptor tyrosinebased inhibition motif (ITIM), implying that FCRL6 transmits inhibitory signaling cascades. A recent study identified high levels of FCRL6 on NK cells in HLA-II + solid tumor environment, and expression of HLA-DR molecules on the surface of K562 cells inhibited the cytotoxic function of FCRL6 + NK-92 cells (Johnson et al, 2018). Interestingly, FCRL6 is down-modulated on the surface of NK cells upon exposure to IL-2 and IL-15 (Wilson et al, 2007), in contrast to NKp44, which expression is induced after stimulation with these cytokines.…”

Section: Hla Class II Molecules Can Serve As Ligands For Nk Cell Recementioning

confidence: 97%

“…The level of HLA-II expression within the tumor environment can predict patient responses toward anti-PD-1 immunotherapy (Johnson et al, 2016). Interestingly, high FCRL6 expression has been detected on NK cells within HLA-II + solid tumors, and blocking of FCRL6 increased the functional response of NK cells as well as T cells toward HLA-DR + tumor cells (Johnson et al, 2018). In addition, FCRL6 levels were elevated at relapse within patients that progressed under anti-PD-1therapy (Johnson et al, 2018).…”

Section: Hla-ii Molecules In Malignancies and Auto-inflammatory Diseasesmentioning

confidence: 99%

“…Interestingly, high FCRL6 expression has been detected on NK cells within HLA-II + solid tumors, and blocking of FCRL6 increased the functional response of NK cells as well as T cells toward HLA-DR + tumor cells (Johnson et al, 2018). In addition, FCRL6 levels were elevated at relapse within patients that progressed under anti-PD-1therapy (Johnson et al, 2018). Therefore, the authors suggested the possibility of a combined immune checkpoint inhibitor treatment, targeting both PD-1 and FCRL6, to boost cytotoxic immune cell responses.…”

Section: Hla-ii Molecules In Malignancies and Auto-inflammatory Diseasesmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of NK-Cell Function by HLA Class II

Niehrs

Altfeld

2020

Front. Cell. Infect. Microbiol.

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Natural Killer (NK) cells were initially described as part of the innate immune system and characterized by their ability to lyse malignant and virus-infected cells. The cytolytic function of NK cells is tightly controlled by activating and inhibitory receptors expressed on the cell surface. Ligands that interact with a variety of NK-cell receptors include the human leukocyte antigen (HLA) molecules, and the regulation of NK-cell function by HLA class I molecules is well-established. Earlier studies also suggested a role of HLA class II molecules in regulating NK cell activity; yet, interactions between HLA class II molecules and NK cell receptors have not been well-characterized. We recently identified a subset of HLA-DP molecules that can serve as ligands for the natural cytotoxicity receptor NKp44 and activate NK cells. This novel receptor-ligand interaction provides a potential mechanism to explain the strong associations of HLA-DP molecules with HBV infection outcomes, graft-vs.-host disease and inflammatory bowel disease. Furthermore, it adds a new mechanism for NK-cell crosstalk with immune cells expressing HLA class II molecules. In this perspective article, we discuss the potential implications of NK cell receptor interactions with HLA class II molecules for the regulation of immune responses.

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Tumor-specific MHC-II expression drives a unique pattern of resistance to immunotherapy via LAG-3/FCRL6 engagement

Cited by 133 publications

References 58 publications

Functional systemic CD 4 immunity is required for clinical responses to PD ‐L1/ PD ‐1 blockade therapy

Functional systemic CD 4 immunity is required for clinical responses to PD ‐L1/ PD ‐1 blockade therapy

Functional systemic CD4 immunity is a differential factor for clinical responses to PD-L1/PD-1 blockade therapy in lung cancer

Regulation of NK-Cell Function by HLA Class II

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