**5. Immunologic relative host response and factors influencing the susceptibility of dogs to CTVT**

The CTVT mass grows mostly on male and female external genital areas due to live cell transmission during coitus. The highest risk periods are the estrus and breeding periods. No breed predisposition has been documented, but mixed breed dogs were reported in 41% [19] to 100% [11] of cases. Dogs of any age are susceptible to CTVT. CTVT is most commonly found in intact dogs between two and five years of age. The mean ages of the affected dogs were 3.9–4.5 [13]. GTVT is never found in virgin dogs. Also, the tumor is more common in females than males due to one infected male often interacting with many females, both in breeding kennels and endemic areas [13]. Older dogs showed more ETVT evidence than GTVT, which is more common in intact young adult dogs. Poor body condition scores and immune status might be cofactors in aging dogs with ETVT [11].

Researchers have been interested in and attended the roles of host immunity response in the P-phase and R-phase of CTVT. In experimental transplantation, CTVT can evade immune surveillance and show rapid growth for 12 weeks. The spontaneous regression of both natural and experimental transplantation suggests that the host immune response plays a major role in CTVT. Moreover, immunosuppressed dogs and puppies develop more aggressive CTVT masses that lack TILs, and these masses are rarely eliminated and hardly show complete remission [2]. The differences between the P-phase and the R-phase are the presence and number of TILs. Thus, the complete regression and complete response to treatment may depend on the appropriate immune response of host cells, which is related to the immune status of the CTVT-susceptible dogs. CTVT cells evade immune detection during the transmission period and growth phase by secretion of transforming growth factor β (TGF-β). TGF-β is a multifunctional protein that controls cellular differentiation and proliferation, which acts as a suppression activity of class I and II MHC expression and natural killer (NK) cell activity. Conversely, TGF-β is countered by interleukin-6 (IL-6), which is produced by TILs [20, 37].

CTVT cells show the tumor-associated antigen and shed into the circulation during the P-phase, and this CTVT tumor-associated antigen could no longer be detected after surgical removal of the CTVT mass [13]. This CTVT tumor-associated antigen was detected using antibodies against the antigen during the P, S, and R phases [38]. The amount of this antigen released in the host circulation increased alongside the increase in tumor volume. There is evidence that humoral immunity plays a role in the P-phase. This antigen may be responsible for blocking the host's immune response in the P-phase. The infiltration, the presence of B cells, and the upregulated expression of the groups of genes related to B cells were mentioned in the signature of acute allograft rejection [13]. Thus, humoral immunity also plays an important role in inhibiting and preventing CTVT tumor development and acute CTVT allograft rejection in many case studies. This emphasizes that CTVT itself has been reported to be antigenic and can evoke tumor rejection in the host's immunity.

In naturally occurring CTVT, spontaneous regression was also observed, albeit less frequently than in the experimental transplanted CTVT [32]. The dogs that have recovered are immune to reinoculation [1]. Passive immune transfer of post-regression sera to CTVT-bearing dogs has been shown to inhibit and prevent tumor development. Moreover, the growth of CTVT is inhibited in puppies born to dams that are immunized for CTVT before or during pregnancy [2]. CTVT cells have more membrane-bound antibodies in the S and R phases than in the P-phase.

*Canine Transmissible Venereal Tumor: An Infectious Neoplasia in Dogs DOI: http://dx.doi.org/10.5772/intechopen.106150*

The absence of antibodies in puppies with metastasis suggest the importance of humoral immunity in progression. The metastatic rate is low—less than 20% in GTVT cases [9, 19]. Metastatic cases have been reported in subcutaneous tissues, skin, lymph nodes, eyes, tonsils, liver, spleen, oral mucosa, nasal mucosa, brain, and bone marrow [15, 21, 32, 39]. Although metastasis is not common in CTVT cases, it can be a serious situation and the cause of death.
