T-helper and T-regulatory cells modulation in head and neck squamous cell carcinoma

Figures & data

Figure 1. Cytokines modulation during HNSCC progression. HNSCC development is characterized by the progressive decline of Th1 related cytokine INFγ. Conversely, IL-23 levels increase steadily, probably as the result of an inflammatory response against cancer. Nevertheless, as HNSCC progresses, a significant rise of TGFβ and a concomitant decrease of IL-23 levels promote Treg differentiation with a consequent decline of Th17 cells. As a result, in the latest phase of HNSCC progression, anti-inflammatory and anti-immune cytokines such as IL-4 and IL-10 prevail.

Table 1. Studies evaluating T-helper cells modulation in HNSCC.

Specimens	Methods	Main findings	Reference
45 HNSCC, stage I–IV	Flow cytofluorimetric analysis of PBMC	Decrease of CD11^+ DC, increase of Th1 and Th2 cells, no variation in Th1/Th2 ratio	^21
42 HNSCC stage I–IV	Flow cytofluorimetric analysis of PBMC	Decrease of total CD4^+ T cells, increase of Th1 and Th2 cells (upon PHA stimulation), no variation in Th1/Th2 cells	^61
10 HNSCC stage III–IV	Flow cytofluorimetric analysis of PBMC	Reduced count of total white cells, reduction of CD4^+ and CD8^+ T cells	^9
12 OSCC	Flow cytofluorimetric analysis of PBMC	No variation in CD4^+ and CD8^+ T cells	^51
25 HNSCC, stage not specified	Flow cytofluorimetric analysis of PBMC and TIL	Increase amount of circulating and infiltrating TH17 cells, decrease of circulating Th1 cells, decrease of Th1/Th17 cells ratio	^29
25 HNSCC, stage not specified	Flow cytofluorimetric analysis of peripheral blood and tumor infiltrating CD4^+ T-helper cells	Decrease of circulating and infiltrated CD161^+ Th17 cells, decrease of CD161^+ Th17 cells in metastatic HNSCC	^19
67 HNSCC, stage I-IV	Flow cytofluorimetric analysis of peripheral blood Th17	Increased levels of Th17 cells, correlating to tumor stage	^30
54 HNSCC, stage I–IV	Flow cytofluorimetric analysis of PBMC	Increase amount of CD8^+ anCD4^+ T cells in HPV+ specimens	^15
42 Laryngeal SCC, stage I–IV	Flow cytofluorimetric analysis of PBMC	No variation in CD4^+ and CD8^+ T cells, Th1 cells decrease	^20
30 OSCC, stage I–IV	Flow cytofluorimetric analysis of peripheral bloodand tumor infiltrating T lymphocytes	Decrease of circulating and infiltrating CD4^+ T cells	^13
162 OSCC, stage I-IV, HPV^+ vs. HPV^− tumors	Immunofluorescence staining for CD3 and IL-17 in TIL	Higher levels of CD3^+ T cells and Th17 cells in HPV^+ tumors	^33

Table 2. Studies analyzing T-helper-related cytokines in HNSCC.

Specimens	Methods	Main findings	References
101 HNSCC, stage I–IV	ELISA analysis of serum cytokine levels	Increased levels of IL-1b, IL-2, IL-4, IL-6, IL-10. Decreased levels of INFγ	^28
58 HNSCC, stage I–IV	ELISA analysis of serum cytokine levels	Increased IL-6, IL-10 levels, positive correlation to stage. Increased levels of IL-12, negative correlation to stage	^25
55 pre-surgical HNSCC	ELISA analysis of serum cytokine levels	Increase levels of IL-12, decreased level of IL-10	^26
10 HNSCC stage III–IV	ELISA analysis on culture supernatant of HNSCC PBMC	Increase levels of IL-4 and IL-10	^9
25 HNSCC, stage not specified	Flow cytometric analysis on cancer cell suspension and TIL	High amount of IL-1b, IL-23 and IL-6 positive cells in tumor tissue	^29
150 HNSCC, stage I–IV	ELISA analysis on serum of HNSCC patients pre- vs. post-treatment	IL-10 detected in more HNSCC patients than in healthy controls, no differences between pre-treatment or post-treatment	^27
17 larynx SCC, 6 larynx dysplasia	Flow cytofluorimetric analysis on serum	Increased levels of IL-6, IL-8, IL-10 in both SCC and dysplasia	^22
Premalignant oral lesion and OSCC, stage II–IV	Flow cytofluorimetric analysis of cytokine in plasma, tissue lysate and supernatants of dissociated tissue	Increased levels of IL-2, IL-6, IL-17 and INFγ in premalignant lesions	^32
78 OSCC, mainly stage III–IV	ELISA analysis of serum cytokine levels	Increased levels of IL-2, IL-4, IL-10, INFγ and TGFβ	^23
34 premalignant oral lesion, 61 HNSCC, stage II–IV	Cytometric array analysis of plasma and tissue lysate	Increased levels of IL-6 and IL-17 in premalignant lesion and in HNSCC	^31

Table 3. Ongoing trials for anti-ICRs antibodies in HNSCC immunotherapy.

Trial NCT	Phase	No. of patients	Status	Elegibility	Treatment	Primary end point
NCT02475213	Phase I	75	Recruiting	Refractory cancers, including HNSCC	Pembrolizumab + Enoblituzumab	AE, plasma levels, anti-antibodies, tumor volume
NCT02626000	Phase I	40	Recruiting	Recurrent or metastatic HNSCC	Pembrolizumab + Talimogene laherparepvec	AE, dose-limiting toxicity, ORR, OS
NCT02819752	Phase I	36	Not yet recruiting	Advanced HNSCC	Pembrolizumab + cisplatin	AE, OS
NCT02586207	Phase I	39	Recruiting	HNSCC	Pembrolizumab + cisplatin + RT	AE
NCT02775812	Phase I	56	Recruiting	Stage III–IV HNSCC	Pembrolizumab + cisplatin + RT	Acute toxicity, expression of peripheral immune-inflammatory markers, distant metastasis, OS,
NCT02718820	Phase I/II	22	Recruiting	Recurrent or metastatic HNSCC	Pembrolizumab + docetaxel	ORR, AE, OS,
NCT02452424	Phase I/II	400	Recruiting	Melanoma + HNSCC	Pembrolizumab + PLX3397	ORR
NCT02521870	Phase I/II	156	Recruiting	Recurrent or metastatic HNSCC	Pembrolizumab + SD-101	dose limiting toxicity, PFS, OS
NCT02289209	Phase II	48	Recruiting	Inoperable or second primary HNSCC	Pembrolizumab + RT	Acute AE, PFS, OS
NCT02609503	Phase II	29	Recruiting	Advanced HNSCC	Pembrolizumab + RT	PFS, OS
NCT02454179	Phase II	74	Active not recruiting	Advanced HNSCC	Pembrolizumab + Acalabrutinib	ORR
NCT02255097	Phase II	172	Active not recruiting	Recurrent or metastatic HNSCC	Pembrolizumab + cetuximab + cisplatin	ORR, AE, OS,
NCT02707588	Phase II	114	Not yet recruiting	Advanced HNSCC	Pembrolizumab + cetuximab + RT	AE, OS
NCT02892201	Phase II	24	Recruiting	HNSCC	Pembrolizumab	OR, reduction of PD-L1 expression, AE, OS
NCT02841748	Phase II	100	Not yet recruiting	Potential recurrent HNSCC	Pembrolizumab	OS, PFS
NCT02296684	Phase II	46	Recruiting	Surgically resectable HNSCC	Pembrolizumab + RT	AE, locoregional control
NCT02252042	Phase III	466	Active not recruiting	Recurrent or metastatic HNSCC	Pembrolizumab vs. methotrexate, docetaxel, cetuximab	ORR, PFS, PD-L1 ligand, OS
NCT02358031	Phase III	825	Active not recruiting	Recurrent or metastatic HNSCC	Pembrolizumab vs. Pembrolizumab + cisplatin or 5-FU or cetuximab	PD-L1 expression, PFS, OS
NCT03040999	Phase III	780	Not yet recruiting	Advanced HNSCC	Pembrolizumab vs. cisplatin + RT	AE, OS
NCT02827838	na	20	Recruiting	Oral cavity and oropharynx cancer	Durvalumab	AE
NCT02262741	Phase I	69	Active not recruiting	HNSCC	Durvalumab + Tremelimumab	AE, ORR
NCT02658214	Phase I	60	Active not recruiting	Advanced solid tumors including HNSCC	Durvalumab + Tremelimumab ± paclitaxel, carboplatin, 5-FU	AE
NCT02264678	Phase I	114	Recruiting	Solid tumors including HNSCC	Durvalumab + AZD6738	AE, ORR, PFS
NCT01938612	Phase I	264	Recruiting	Solid tumors including HNSCC	Durvalumab or Tremelimumab	MTD, AE, ORR, PFS, OS
NCT02499328	Phase I/II	147	Recruiting	Advanced and metastatic HNSCC	Durvalumab ± AZD9150 or AZD5069	MTD, AE, ORR
NCT03019003	Phase I/II	59	Not yet recruiting	Recurrent or metastatic HNSCC	Durvalumab + Tremelimumab, azacitidine	ORR, PFS, OS
NCT02207530	Phase II	112	Active not recruiting	Recurrent or metastatic PD-L1 positive HNSCC	Durvalumab	ORR, PFS, OS
NCT02319044	Phase II	543	Active not recruiting	Recurrent or metastatic HNSCC	Durvalumab ± Tremelimumab	ORR, PFS, DCR, OS
NCT02369874	Phase III	720	Recruiting	Recurrent or metastatic PD-L1 positive HNSCC	Durvalumab ± Tremelimumab vs. standard chemotherapy	ORR, PFS, DCR, OS
NCT02551159	Phase III	760	Recruiting	Recurrent or metastatic HNSCC	Durvalumab ± Tremelimumab vs. standard chemotherapy (cisplatin, 5-FU, cetuximab)	ORR, PFS. OS
NCT02471846	Phase I	276	Recruiting	Advanced solid tumors including HNSCC	Atelizumab or GDC-0919	Dose-limiting toxicity, AE
NCT02764593	Phase I	120	Recruiting	High risk, advanced HNSCC	Nivolumab + cetuximab + cisplatin + RT	Dose-limiting toxicity
NCT02903914	Phase I	236	Recruiting	Solid tumors including HNSCC	Nivolumab + CB-1158	MTD
NCT02988960	Phase I	180	Recruiting	Solid tumors including HNSCC	Nivolumab + ABBV-927	MTD, ORR, PFS
NCT02124850	Phase I	24	Recruiting	HNSCC	Nivolumab ± motolimod vs. cetuximab + motolimod	Immune biomarkers: FcγR genotype, NK activation, tumor infiltration and serum cytokines, T-cell activation
NCT02834247	Phase I	120	Recruiting	Solid tumors including HNSCC	Nivolumab + TAK-659	MTD, AE, ORR, PFS, OS
NCT02636036	Phase I	30	Recruiting	Metastatic epithelia tumors including HNSCC	Nivolumab + enadenotucirev	MTD
NCT02335918	Phase I/II	205	Recruiting	Refractory cancers, including HNSCC	Nivolumab + varlilumab	Dose-limiting toxicity, ORR, OS
NCT03003637	Phase I/II	32	Not yet recruiting	Advanced or recurrent HNSCC	Nivolumab + ipilimubab	Toxicity, tumor response,
NCT02684253	Phase II	40	Recruiting	metastatic HNSCC	Nivolumab + RT	Best overall response
NCT02823574	Phase II	315	Recruiting	Recurrent or metastatic HNSCC	Nivolumab + ipilimumab	ORR, PFS, OS
NCT02105636	Phase III	506	Active not recruiting, with results	Recurrent or metastatic HNSCC	Nivolumab vs. cetuximab or methotrexate or docetaxel	ORR, PFS, OS
NCT02741570	Phase III	490	Recruiting	Recurrent or metastatic HNSCC	Nivolumab ± ipilimubab vs. cisplatin + cetuximab	ORR, PFS, OS, PD-L1 expression

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