The online version of this article (https://doi.org/10.1007/s00262-020-02497-9) contains supplementary material, which is available to authorized users.
Satu Mustjoki and Anna Kreutzman equal contribution.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Anti-PD1 treatment has improved the survival of metastatic melanoma patients, yet it is unknown which patients benefit from the treatment. In this exploratory study, we aimed to understand the effects of anti-PD1 therapy on the patients’ immune system and discover the characteristics that would result in successful treatment. We collected peripheral blood (PB) samples from 17 immuno-oncology-naïve metastatic melanoma patients before and after 1 and 3 months of anti-PD1 therapy. In addition, matching tumor biopsies at the time of diagnosis were collected for tissue microarray. The complete blood counts, PB immunophenotype, serum cytokine profiles, and tumor-infiltrating lymphocytes were analyzed and correlated with the clinical data. Patients were categorized based on their disease control into responders (complete response, partial response, stable disease > 6 months, N = 11) and non-responders (progressive disease, stable disease ≤ 6 months, N = 6). During therapy, the PB natural killer T (NKT) cell frequency, expression of CD25 and CD45RO on cytotoxic natural killer (NK) cells, and serum CXC chemokine levels were significantly increased in responders. Furthermore, higher age together with age-associated characteristics from PB, lower frequency of PB-naïve CD8+ T cells, and elevated levels of serum MCP-4 and OPG were discovered as baseline predictors of treatment response. We therefore propose that in addition to T cells, anti-PD1 treatment is associated with NK- and NKT-cell population dynamics, and that the age-associated characteristics from PB together with older age may contribute to prolonged PFS in anti-PD1-treated melanoma patients.
Carreau N, Pavlick A (2019) Revolutionizing treatment of advanced melanoma with immunotherapy. Surg Oncol [Epub ahead of print]
Holsken O, Miller M, Cerwenka A (2015) Exploiting natural killer cells for therapy of melanoma. J Dtsch Dermatol Ges 13:23–29 PubMed
Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbe C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320–330 PubMedCrossRefPubMedCentral
Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J (2015) Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16:375–384 PubMedPubMedCentralCrossRef
Larkin J, Minor D, D'Angelo S, Neyns B, Smylie M, Miller WH Jr, Gutzmer R, Linette G, Chmielowski B, Lao CD, Lorigan P, Grossmann K, Hassel JC, Sznol M, Daud A, Sosman J, Khushalani N, Schadendorf D, Hoeller C, Walker D, Kong G, Horak C, Weber J (2018) Overall survival in patients with advanced melanoma who received nivolumab versus investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol 36:383–390 PubMedCrossRef
Bae EA, Seo H, Kim IK, Jeon I, Kang CY (2019) Roles of NKT cells in cancer immunotherapy. Arch Pharm Res 11:1–6
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247 CrossRef
Pesce S, Greppi M, Tabellini G, Rampinelli F, Parolini S, Olive D, Moretta L, Moretta A, Marcenaro E (2017) Identification of a subset of human natural killer cells expressing high levels of programmed death 1: a phenotypic and functional characterization. J Allergy Clin Immunol 139:335–346.e3 PubMedCrossRef
Hsu J, Hodgins JJ, Marathe M, Nicolai CJ, Bourgeois-Daigneault MC, Trevino TN, Azimi CS, Scheer AK, Randolph HE, Thompson TW, Zhang L, Iannello A, Mathur N, Jardine KE, Kirn GA, Bell JC, McBurney MW, Raulet DH, Ardolino M (2018) Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J Clin Investig 128:4654–4668 PubMedCrossRef
Krzywinska E, Cornillon A, Allende-Vega N, Vo DN, Rene C, Lu ZY, Pasero C, Olive D, Fegueux N, Ceballos P, Hicheri Y, Sobecki M, Rossi JF, Cartron G, Villalba M (2016) CD45 isoform profile identifies natural killer (NK) subsets with differential activity. PLoS ONE 11:e0150434 PubMedPubMedCentralCrossRef
Krzywinska E, Allende-Vega N, Cornillon A, Vo DN, Cayrefourcq L, Panabieres C, Vilches C, Dechanet-Merville J, Hicheri Y, Rossi JF, Cartron G, Villalba M (2015) Identification of anti-tumor cells carrying natural killer (NK) cell antigens in patients with hematological cancers. EBioMedicine 2:1364–1376 PubMedPubMedCentralCrossRef
Kugel CH 3rd, Douglass SM, Webster MR, Kaur A, Liu Q, Yin X, Weiss SA, Darvishian F, Al-Rohil RN, Ndoye A, Behera R, Alicea GM, Ecker BL, Fane M, Allegrezza MJ, Svoronos N, Kumar V, Wang DY, Somasundaram R, Hu-Lieskovan S, Ozgun A, Herlyn M, Conejo-Garcia JR, Gabrilovich D, Stone EL, Nowicki TS, Sosman J, Rai R, Carlino MS, Long GV, Marais R, Ribas A, Eroglu Z, Davies MA, Schilling B, Schadendorf D, Xu W, Amaravadi RK, Menzies AM, McQuade JL, Johnson DB, Osman I, Weeraratna AT (2018) Age correlates with response to anti-PD1, reflecting age-related differences in intratumoral effector and regulatory T-cell populations. Clin Cancer Res 24:5347–5356 PubMedPubMedCentralCrossRef
- Age-associated changes in the immune system may influence the response to anti-PD1 therapy in metastatic melanoma patients
- Springer Berlin Heidelberg
Cancer Immunology, Immunotherapy
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
Neu im Fachgebiet Onkologie
Mail Icon II