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

Miren Zuazo, Hugo Arasanz, Gonzalo Fernandez-Hinojal, Maria Jesus Garcia-Granda, Maria Gato, Ana Bocanegra, Berta Hernandez, Maite Martinez, Lucia Teijeira, Idoia Morilla, Maria Jose Lecumberri, Angela Fernandez de Lascoiti, Ruth Vera, Grazyna Kochan, David Escors
doi: https://doi.org/10.1101/508739
Miren Zuazo
1 Fundacion Miguel Servet;
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Hugo Arasanz
2 Complejo Hospitalario de Navarra
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Gonzalo Fernandez-Hinojal
2 Complejo Hospitalario de Navarra
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Maria Jesus Garcia-Granda
1 Fundacion Miguel Servet;
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Maria Gato
1 Fundacion Miguel Servet;
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Ana Bocanegra
1 Fundacion Miguel Servet;
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Berta Hernandez
2 Complejo Hospitalario de Navarra
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Maite Martinez
2 Complejo Hospitalario de Navarra
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Lucia Teijeira
2 Complejo Hospitalario de Navarra
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Idoia Morilla
2 Complejo Hospitalario de Navarra
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Maria Jose Lecumberri
2 Complejo Hospitalario de Navarra
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Angela Fernandez de Lascoiti
2 Complejo Hospitalario de Navarra
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Ruth Vera
2 Complejo Hospitalario de Navarra
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Grazyna Kochan
1 Fundacion Miguel Servet;
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David Escors
1 Fundacion Miguel Servet;
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  • For correspondence: descorsm@navarra.es
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Abstract

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, co-expressed low levels 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 circulating lung cancer antigen-specific CD4 and CD8 T cells. CD4 T cells in these patients proliferated very poorly, strongly co-upregulated PD-1/LAG-3 after stimulation, and were largely refractory to PD-1 monoblockade ex vivo and in vivo. Although baseline CD8 immunity was strongly dysfunctional in all patients before the start of therapy, it only recovered in patients with functional CD4 immunity. CD4 and CD8 T cell dysfunctionality was caused by PD-1/LAG-3 co-expression, which could be reverted by PD-1/LAG-3 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.

Footnotes

  • Correction in the author affiliations. Inclusion of validation dataset.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 09, 2019.
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Functional systemic CD4 immunity is a differential factor for clinical responses to PD-L1/PD-1 blockade therapy in lung cancer
Miren Zuazo, Hugo Arasanz, Gonzalo Fernandez-Hinojal, Maria Jesus Garcia-Granda, Maria Gato, Ana Bocanegra, Berta Hernandez, Maite Martinez, Lucia Teijeira, Idoia Morilla, Maria Jose Lecumberri, Angela Fernandez de Lascoiti, Ruth Vera, Grazyna Kochan, David Escors
bioRxiv 508739; doi: https://doi.org/10.1101/508739
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Functional systemic CD4 immunity is a differential factor for clinical responses to PD-L1/PD-1 blockade therapy in lung cancer
Miren Zuazo, Hugo Arasanz, Gonzalo Fernandez-Hinojal, Maria Jesus Garcia-Granda, Maria Gato, Ana Bocanegra, Berta Hernandez, Maite Martinez, Lucia Teijeira, Idoia Morilla, Maria Jose Lecumberri, Angela Fernandez de Lascoiti, Ruth Vera, Grazyna Kochan, David Escors
bioRxiv 508739; doi: https://doi.org/10.1101/508739

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