Neoadjuvant immunotherapy of oral squamous cell carcinoma modulates intratumoral CD4/CD8 ratio and tumor microenvironment: a multicenter phase II clinical trial.
OBJECTIVE
To investigate the clinicopathologic effects of local neoadjuvant Leukocyte Interleukin Injection (LI) regimen in oral squamous cell carcinoma (OSCC) patients. Treatment regimen included LI 800 IU/d as interleukin-2 (IL-2), administered half peritumorally and half perilymphatically five times per week for 3 weeks; low-dose cyclophosphamide; indomethacin; zinc; and multivitamins.


METHODS
Thirty-nine patients diagnosed with T2-3N0-2M0 OSCC participated in the pathology portion of this phase II multicenter study (19 LI-treated patients and 20 historical controls). Clinical responses were determined by imaging. Paraffin-embedded tumor samples were obtained at surgery for all patients. Surgery for the LI-treated group was performed between days 14 and 54 after the end of treatment. Histologic evaluation, pathologic staging, necrosis, and American Joint Committee on Cancer grading were performed from hematoxylin and eosin sections. Immunohistochemistry and morphometry determined cellular infiltrate.


RESULTS
Two pathologically complete, two major (> 50%), and four minor responses (> 30% but < 50%) resulted from LI treatment (overall response rate, 42%). Histopathology showed that the intratumoral CD4+:CD8+ ratio was low (< 1) in patients not treated with LI (controls). An increase in tumor-infiltrating CD4+ and a decrease of CD8+ T cells was observed in LI-treated patients, leading to a significantly (P < .05) higher intratumoral CD4+:CD8+ ratio (> 2.5). This was paralleled by dendritic cell transition from tumor surface toward stromal interface (P < .05), with macrophage decrease and neutrophil accumulation, multifocal microscopic necrosis, and significant (P < .05) increase in tumor stroma of LI-treated patients compared with controls.


CONCLUSIONS
LI-treated OSCC patients were characterized by a markedly altered composition of tumor-infiltrating mononuclear cells, increased CD4+:CD8+ ratio, and increased tumor stroma to epithelial ratio, all of which were distinct from controls.
Tímár
József
J
National Institute of Oncology, Department of Otolaryngology and Head and Neck Surgery, Semmelweis University, Budapest, Hungary.
Ladányi
Andrea
A
Forster-Horváth
Csaba
C
Lukits
Júlia
J
Döme
Balázs
B
Remenár
Eva
E
Godény
Mária
M
Kásler
Miklós
M
Bencsik
Beáta
B
Répássy
Gábor
G
Szabó
György
G
Velich
Norbert
N
Suba
Zsuzsa
Z
Elo
János
J
Balatoni
Zsuzsa
Z
Pócza
Károly
K
Zemplén
Béla
B
Chretien
Paul
P
Talor
Eyal
E
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001707:Biopsy, Needle; D016516:CD4-CD8 Ratio; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D003520:Cyclophosphamide / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods; D007213:Indomethacin / Q000627:therapeutic use; D015552:Injections, Intralesional; D007376:Interleukin-2 / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D015996:Survival Rate; D016896:Treatment Outcome
D007376:Interleukin-2; D003520:Cyclophosphamide; D007213:Indomethacin