Inclusion Criteria:
1. Patients with squamous cell carcinoma of the head and neck region, (including mucosal,cutaneous, or nodal) who are planned for surgical resection and in the opinion of the investigator are able to safely undergo neoadjuvant anti-PD-1 and radiation. In addition, the following are eligible (but will not contribute toward total accrual): non-surgical cases that are planned for palliative RT or that refuse or are unfit for definitive concurrent chemotherapy.
2. HPV status as determined by p16 immunostain
3. Cohort 3: HPV-positive patients only
4. Cohort 4: HPV-negative patients only
5. Age 18 years or above with ability to give informed consent, comply with the protocol, and sign a study-specific consent document. Patients with history of psychiatric illness must be judged by the investigator as able to understand the investigational nature and risks associated with the therapy.
6. Eastern Cooperative Oncology Group (ECOG) performance status deemed suitable by investigator for study requirements.
7. Laboratory values (most recent), must be within 6 weeks of week 0 on study:
* WBC ≥ 2000/uL, ANC ≥ 1000/uL
* Hgb \> 8g/dL (patients may be transfused to reach this level)
* Platelets \> 50,000 cells/mm3
* Creatinine ≤ 3 x ULN
* AST/ALT ≤ 5 x ULN for subjects without liver metastasis; or ≤ 8 x ULN for subjects with liver metastasis, \[per investigator brochure\]
* Total bilirubin ≤ 3 x ULN, (except subjects with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
* Negative pregnancy test (bHCG urine or serum, women of childbearing potential only)
8. Women of child-bearing potential (WOCBP) must agree to follow adequate contraceptive practices to avoid pregnancy for the duration of treatment with nivolumab plus 5 half-lives of nivolumab (75 days) plus 30 days (duration of ovulatory cycle) for a total of 105 days post-treatment completion.
9. Males who are sexually active with WOCBP must agree to follow adequate contraceptive practices to avoid pregnancy for the duration of treatment with study drug (s) plus 5 half lives of the study drug (75 days) plus 90 days (duration of sperm turnover) for a total of 165 days post-treatment completion.
Exclusion Criteria:
1. Any clinical factors such as bleeding, active infection, or psychiatric factors that in the judgment of the investigator would preclude safe participation and compliance with study procedures.
2. HNSCC for which radiation is not indicated during normal treatment course.
3. Need for chronic maintenance with oral steroids ≥20mg daily prednisone equivalent; inhaled, topical or non-absorbed steroids are acceptable.
4. History of or current active autoimmune disease, \[e.g. including but not limited to inflammatory bowel diseases \[IBD\], rheumatoid arthritis, autoimmune hepatitis, systemic sclerosis (scleroderma and variants), systemic lupus erythematosus, autoimmune vasculitis, autoimmune neuropathies (such as Guillain-Barre syndrome)\], which in the judgment of the investigator poses an active and significant morbidity risk. Vitiligo and adequately controlled endocrine deficiencies such as hypothyroidism are not exclusionary. Patient and investigator may opt to accept risk of autoimmune disease flare, based on shared-decision making with consideration of risk/benefit.
